Pyrazol-4-yl-heterocyclyl-carboxamide compounds and methods of use

ABSTRACT

Pyrazol-4-yl-heterocyclyl-carboxamide compounds of Formula I, including stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein X is a thiazolyl, picolinyl, pyridinyl, or pyrimidinyl, are useful for inhibiting Pim kinase, and for treating disorders such as cancer mediated by Pim kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 13/834,316 filed onMar. 15, 2013 which is a divisional of U.S. Ser. No. 13/080,762 filed on6 Apr. 2011, and claims the benefit under 35 USC §119(e) of U.S.Provisional Application Ser. No. 61/321,588 filed on 7 Apr. 2010, whichis incorporated by reference in entirety

FIELD OF THE INVENTION

The invention relates generally to pyrazol-4-yl-heterocyclyl-carboxamidecompounds for treating disorders mediated by Pim kinase (Pim-1, Pim-2,and/or Pim-3) inhibitors, thus useful as cancer therapeutics. Theinvention also relates to compositions, more specifically pharmaceuticalcompositions comprising these compounds and methods of using the same,either alone or in combination, to treat various forms of cancer andhyperproliferative disorders, as well as methods of using the compoundsfor in vitro, in situ, and in vivo diagnosis or treatment of mammaliancells, or associated pathological conditions.

BACKGROUND OF THE INVENTION

Pim kinases are family of three highly-related serine and threonineprotein kinases encoded by the genes Pim-1, Pim-2, and Pim-3. The genenames are derived from the phrase

Proviral Insertion, Moloney, frequent integration sites for murinemoloney virus wherein the insertions lead to overexpression of Pimkinases and either de novo T-cell lymphomas, or dramatic acceleration oftumorigenesis in a transgenic Myc-driven lymphoma model (Cuypers et al.(1984) Cell, vol. 37 (1) pp. 141-50; Selten et al. (1985) EMBO J. vol. 4(7) pp. 1793-8; van der Lugt et al. (1995) EMBO J. vol. 14 (11) pp.2536-44; Mikkers et al. (2002) Nature Genetics, vol. 32 (1) pp. 153-9;van Lohuizen et al. (1991) Cell, vol. 65 (5) pp. 737-52). Theseexperiments reveal synergy with the oncogene c-Myc, and suggest thatinhibition of the Pim kinases may have therapeutic benefit.

Mouse genetics suggests that antagonizing Pim kinases may have anacceptable safety profile; a Pim 1−/−; Pim-2−/−, Pim-3−/− mouse knockoutis viable although slightly smaller than wild type littermates (Mikkerset al. (2004) Mol Cell Biol vol. 24 (13) pp. 6104-154). The three genesgive rise to six protein isoforms including a protein kinase domain, andapparently without recognizable regulatory domains. All six isoforms areconstitutively active protein kinases that do not requirepost-translational modification for activity, thus Pim kinases areregulated primarily at the transcriptional level (Qian et al. (2005) JBiol Chem, vol. 280 (7) pp. 6130-7). Pim kinase expression is highlyinducible by cytokines and growth factors receptors and Pims are directtranscriptional targets of the Stat proteins, including Stat3 and Stat5.Pim-1, for example, is required for the gp130-mediated Stat3proliferation signal (Aksoy et al. (2007) Stem Cells, vol. 25 (12) pp.2996-3004; Hirano et al. (2000) Oncogene vol. 19 (21) pp. 2548-56;Shirogane et al. (1999) Immunity vol. 11 (6) pp. 709-19).

Pim kinases function in cellular proliferation and survival pathwaysparallel to the PI3k/Akt/mTOR signaling axis (Hammerman et al. (2005)Blood vol. 105 (11) pp. 4477-83). Indeed, several of the phosphorylationtargets of the PI3k axis including Bad and eIF4E-BP1 are cell growth andapoptosis regulators and are also phosphorylation targets of the Pimkinases (Fox et al. (2003) Genes Dev vol. 17 (15) pp. 1841-54; Macdonaldet al. (2006) Cell Biol vol. 7 pp. 1; Aho et al. (2004) FEBS Lettersvol. 571 (1-3) pp. 43-9; Tamburini et al. (2009) Blood vol. 114 (8) pp.1618-27). Pim kinase may affect cell survival since phosphorylation ofBad increases Bcl-2 activity and therefore promotes cell survival.Likewise, phosphorylation of eIF4E-BP1 by mTOR or Pim kinases causesdepression of eIF4E, promoting mRNA translation and cellular growth. Inaddition, Pim-1 has been recognized to promote cell cycle progressionthrough phosphorylation of CDC25A, p21, and Cdc25C (Mochizuki et al.(1999) J Biol Chemvol. 274 (26) pp. 18659-66; Bachmann et al. (2006) IntJ Biochem Cell Biol vol. 38 (3) pp. 430-43; Wang et al. (2002) BiochimBiophys Acta vol. 1593 (1) pp. 45-55.

Pim kinases show synergy in transgenic mouse models with c-Myc-drivenand Akt-driven tumors (Verbeek et al. (1991) Mol Cell Biol vol. 11 (2)pp. 1176-9; Allen et al. Oncogene (1997) vol. 15 (10) pp. 1133-41;Hammerman et al. (2005) Blood vol. 105 (11) pp. 4477-83). Pim Kinasesare involved in transforming activity of oncogenes identified in acutemyeloid leukemia (AML) including Flt3-ITD, BCR-abl, and Tel-Jak2.Expression of these oncogenes in BaF3 cells results in upregulation ofPim-1 and Pim-2 expression, resulting in IL-3 independent growth, andsubsequent Pim inhibition results in apoptosis and cell growth arrest(Adam et al. (2006) Cancer Research vol. 66 (7) pp. 3828-35). Pimoverexpression and dysregulation has also been noted as a frequent eventin many hematopoietic cancers, including leukemias and lymphoma (Amsonet al. (1989) Proc Natl Acad Sci USA vol. 86 (22) pp. 8857-61); Cohen etal. (2004) Leuk Lymphoma vol. 45 (5) pp. 951-5; Hüttmann et al. (2006)Leukemia vol. 20 (10) pp. 1774-82) as well as multiple myeloma (Claudioet al. (2002) Blood vol. 100 (6) pp. 2175-86. Pim 1 has been shown to beoverexpressed and correlated to prostate cancer progression (Cibull etal. (2006) J Clin Pathol vol. 59 (3) pp. 285-8; Dhanasekaran et al.(2001) Nature vol. 412 (6849) pp. 822-6). Pim 1 expression increases inmouse models with disease progression (Kim et al. (2002) Proc Natl AcadSci USA vol. 99 (5) pp. 2884-9). Pim-1 has been reported to be the mosthighly overexpressed mRNA in the subset of human prostate tumor sampleswhich have a c-Myc-driven gene signature (Ellwood-Yen et al. (2003)Cancer Cell vol. 4 (3) pp. 223-38). Pim-3 has been also been shown to beoverexpressed and to have a functional role in pancreatic cancer andhepatocellular carcinoma (Li et al. (2006) Cancer Research vol. 66 (13)pp. 6741-7; Fujii et al. (2005) Int J Cancer, vol. 114 (2) pp. 209-18.

Beyond oncology therapeutic and diagnostic applications, Pim kinasescould play an important role in normal immune system function and Piminhibition could be therapeutic for a number of different immunologicpathologies including inflammation, autoimmune conditions, allergy, andimmune suppression for organ transplantation (Aho et al. Expression ofhuman Pim family genes is selectively up-regulated by cytokinespromoting T helper type 1, but not T helper type 2, celldifferentiation. Immunology (2005) vol. 116 (1) pp. 82-8).

SUMMARY OF THE INVENTION

The invention relates to pyrazol-4-yl-heterocyclyl-carboxamide compoundsfor treating disorders mediated by Pim kinase (Pim-1, Pim-2, and/orPim-3) inhibitors Formula I compounds.

Formula I compounds have the structure:

and stereoisomers, geometric isomers, tautomers, and pharmaceuticallyacceptable salts thereof. The various substituents, including R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, and X are as defined herein.

Formula I compounds include compounds Formula Ia, Ib, Ic, and Id, havingthe structures:

One aspect of the invention is a pharmaceutical composition comprised ofa Formula I compound and a pharmaceutically acceptable carrier, glidant,diluent, or excipient. The pharmaceutical composition may furthercomprise a second chemotherapeutic agent.

Another aspect of the invention is a process for making a pharmaceuticalcomposition which comprises combining a Formula I compound with apharmaceutically acceptable carrier.

The invention includes a method of treating a disease or disorder whichmethod comprises administering a therapeutically effective amount of aFormula I compound to a patient with a disease or disorder selected fromcancer, immune disorders, cardiovascular disease, viral infection,inflammation, metabolism/endocrine function disorders and neurologicaldisorders, and mediated by Pim kinase. The method includes furtheradministering an additional therapeutic agent selected from achemotherapeutic agent, an anti-inflammatory agent, an immunomodulatoryagent, a neurotropic factor, an agent for treating cardiovasculardisease, an agent for treating liver disease, an anti-viral agent, anagent for treating blood disorders, an agent for treating diabetes, andan agent for treating immunodeficiency disorders.

The invention includes a kit for treating a condition mediated by Pimkinase, comprising: a) a first pharmaceutical composition comprising aFormula I compound; and b) instructions for use.

The invention includes a Formula I compound for use as a medicament, andfor use in treating a disease or disorder selected from cancer, immunedisorders, cardiovascular disease, viral infection, inflammation,metabolism/endocrine function disorders and neurological disorders, andmediated by Pim kinase.

The invention includes use of a Formula I compound in the manufacture ofa medicament for the treatment of cancer, immune disorders,cardiovascular disease, viral infection, inflammation,metabolism/endocrine function disorders and neurological disorders, andwhere the medicament mediates Pim kinase.

The invention includes methods of making a Formula I compound.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an exemplary synthesis of 4-aminopyrazole compounds 5 fromnitro-1H-pyrazole 1.

FIG. 2 shows an exemplary synthesis of 4-carboxy-thiazoles 11 fromhydroxamide compounds 6.

FIG. 3 shows an exemplary synthesis of 2-substituted,4-carboxy-5-aminothiazoles 11 by C-2 bromination of 12 followed bySuzuki reaction of 13.

FIG. 4 shows an exemplary synthesis of5-amino-N-(pyrazol-4-yl)thiazole-carboxamide compounds 18 made fromcoupling of 3,4-diaminopyrazole compounds 14 and 2-substituted,4-carboxy-5-aminothiazoles 11.

FIG. 5 shows an exemplary synthesis of6-amino-N-(pyrazol-4-yl)pyridyl-carboxamide compounds 22 made fromcoupling of 3,4-diaminopyrazole compounds 14 and 6-substituted,2-carboxy-3-aminopyridyl compounds 19.

FIG. 6 shows an exemplary synthesis of6-amino-N-(pyrazol-4-yl)picolinic-carboxamide compounds 26 from couplingof 3,4-diaminopyrazole compounds 14 and 5-substituted,3-carboxy-2-aminopicolinyl compounds 23.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. While the invention will be described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments. Onthe contrary, the invention is intended to cover all alternatives,modifications, and equivalents which may be included within the scope ofthe present invention as defined by the claims. One skilled in the artwill recognize many methods and materials similar or equivalent to thosedescribed herein, which could be used in the practice of the presentinvention. The present invention is in no way limited to the methods andmaterials described. In the event that one or more of the incorporatedliterature, patents, and similar materials differs from or contradictsthis application, including but not limited to defined terms, termusage, described techniques, or the like, this application controls.

DEFINITIONS

The term “alkyl” as used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of one to twelve carbonatoms (C₁-C₁₂), wherein the alkyl radical may be optionally substitutedindependently with one or more substituents described below. In anotherembodiment, an alkyl radical is one to eight carbon atoms (C₁-C₈), orone to six carbon atoms (C₁-C₆). Examples of alkyl groups include, butare not limited to, methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl(n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂),1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu,i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl, 1-octyl, and the like.

The term “alkylene” as used herein refers to a saturated linear orbranched-chain divalent hydrocarbon radical of one to twelve carbonatoms (C₁-C₁₂), wherein the alkylene radical may be optionallysubstituted independently with one or more substituents described below.In another embodiment, an alkylene radical is one to eight carbon atoms(C₁-C₈), or one to six carbon atoms (C₁-C₆). Examples of alkylene groupsinclude, but are not limited to, methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—), and the like.

The term “alkenyl” refers to linear or branched-chain monovalenthydrocarbon radical of two to eight carbon atoms (C₂-C₈) with at leastone site of unsaturation, i.e., a carbon-carbon, sp² double bond,wherein the alkenyl radical may be optionally substituted independentlywith one or more substituents described herein, and includes radicalshaving “cis” and “trans” orientations, or alternatively, “E” and “Z”orientations. Examples include, but are not limited to, ethylenyl orvinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), and the like.

The term “alkenylene” refers to linear or branched-chain divalenthydrocarbon radical of two to eight carbon atoms (C₂-C₈) with at leastone site of unsaturation, i.e., a carbon-carbon, sp² double bond,wherein the alkenylene radical may be optionally substituted substitutedindependently with one or more substituents described herein, andincludes radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations. Examples include, but are notlimited to, ethylenylene or vinylene (—CH═CH—), allyl (—CH₂CH═CH—), andthe like.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical of two to eight carbon atoms (C₂-C₈) with at least one site ofunsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynylradical may be optionally substituted independently with one or moresubstituents described herein. Examples include, but are not limited to,ethynyl (—C≡CH), propynyl (propargyl, —CH₂C≡CH), and the like.

The term “alkynylene” refers to a linear or branched divalenthydrocarbon radical of two to eight carbon atoms (C₂-C₈) with at leastone site of unsaturation, i.e., a carbon-carbon, sp triple bond, whereinthe alkynylene radical may be optionally substituted independently withone or more substituents described herein. Examples include, but are notlimited to, ethynylene (—C≡C—), propynylene (propargylene, —CH₂C≡C—),and the like.

The terms “carbocycle”, “carbocyclyl”, “carbocyclic ring” and“cycloalkyl” refer to a monovalent non-aromatic, saturated or partiallyunsaturated ring having 3 to 12 carbon atoms (C₃-C₁₂) as a monocyclicring or 7 to 12 carbon atoms as a bicyclic ring. Bicyclic carbocycleshaving 7 to 12 atoms can be arranged, for example, as a bicyclo[4,5],[5,5], [5,6] or [6,6] system, and bicyclic carbocycles having 9 or 10ring atoms can be arranged as a bicyclo[5,6] or [6,6] system, or asbridged systems such as bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane andbicyclo[3.2.2]nonane. Spiro moieties are also included within the scopeof this definition. Examples of monocyclic carbocycles include, but arenot limited to, cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,cycloundecyl, cyclododecyl, and the like. Carbocyclyl groups areoptionally substituted independently with one or more substituentsdescribed herein.

“Aryl” means a monovalent aromatic hydrocarbon radical of 6-20 carbonatoms (C₆-C₂₀) derived by the removal of one hydrogen atom from a singlecarbon atom of a parent aromatic ring system. Some aryl groups arerepresented in the exemplary structures as “Ar”. Aryl includes bicyclicradicals comprising an aromatic ring fused to a saturated, partiallyunsaturated ring, or aromatic carbocyclic ring. Typical aryl groupsinclude, but are not limited to, radicals derived from benzene (phenyl),substituted benzenes, naphthalene, anthracene, biphenyl, indenyl,indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and thelike. Aryl groups are optionally substituted independently with one ormore substituents described herein.

“Arylene” means a divalent aromatic hydrocarbon radical of 6-20 carbonatoms (C₆-C₂₀) derived by the removal of two hydrogen atom from a twocarbon atoms of a parent aromatic ring system. Some arylene groups arerepresented in the exemplary structures as “Ar”. Arylene includesbicyclic radicals comprising an aromatic ring fused to a saturated,partially unsaturated ring, or aromatic carbocyclic ring. Typicalarylene groups include, but are not limited to, radicals derived frombenzene (phenylene), substituted benzenes, naphthalene, anthracene,biphenylene, indenylene, indanylene, 1,2-dihydronaphthalene,1,2,3,4-tetrahydronaphthyl, and the like. Arylene groups are optionallysubstituted with one or more substituents described herein.

The terms “heterocycle,” “heterocyclyl” and “heterocyclic ring” are usedinterchangeably herein and refer to a saturated or a partiallyunsaturated (i.e., having one or more double and/or triple bonds withinthe ring) carbocyclic radical of 3 to about 20 ring atoms in which atleast one ring atom is a heteroatom selected from nitrogen, oxygen,phosphorus and sulfur, the remaining ring atoms being C, where one ormore ring atoms is optionally substituted independently with one or moresubstituents described below. A heterocycle may be a monocycle having 3to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selectedfrom N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), forexample: a bicyclo[4,5], [5,5], [5,6], or [6,6] system. Heterocycles aredescribed in Paquette, Leo A.; “Principles of Modern HeterocyclicChemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3,4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series ofMonographs” (John Wiley & Sons, New York, 1950 to present), inparticular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960)82:5566. “Heterocyclyl” also includes radicals where heterocycleradicals are fused with a saturated, partially unsaturated ring, oraromatic carbocyclic or heterocyclic ring. Examples of heterocyclicrings include, but are not limited to, morpholin-4-yl, piperidin-1-yl,piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one,pyrrolidin-1-yl, thiomorpholin-4-yl, S-dioxothiomorpholin-4-yl,azocan-1-yl, azetidin-1-yl, octahydropyrido[1,2-a]pyrazin-2-yl,[1,4]diazepan-1-yl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino,thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl,thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl,4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl,dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl,pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyco[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolylquinolizinyl and N-pyridyl ureas. Spiro moieties are also includedwithin the scope of this definition. Examples of a heterocyclic groupwherein 2 ring atoms are substituted with oxo (═O) moieties arepyrimidinonyl and 1,1-dioxo-thiomorpholinyl. The heterocycle groupsherein are optionally substituted independently with one or moresubstituents described herein.

The term “heteroaryl” refers to a monovalent aromatic radical of 5-, 6-,or 7-membered rings, and includes fused ring systems (at least one ofwhich is aromatic) of 5-20 atoms, containing one or more heteroatomsindependently selected from nitrogen, oxygen, and sulfur. Examples ofheteroaryl groups are pyridinyl (including, for example,2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl(including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl,pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl,oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl,benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl,pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl,triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl,benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl,quinoxalinyl, naphthyridinyl, and furopyridinyl. Heteroaryl groups areoptionally substituted independently with one or more substituentsdescribed herein.

The heterocycle or heteroaryl groups may be carbon (carbon-linked), ornitrogen (nitrogen-linked) bonded where such is possible. By way ofexample and not limitation, carbon bonded heterocycles or heteroarylsare bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5,or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline.

By way of example and not limitation, nitrogen bonded heterocycles orheteroaryls are bonded at position 1 of an aziridine, azetidine,pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline,2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline,1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of amorpholine, and position 9 of a carbazole, or β-carboline.

The terms “treat” and “treatment” refer to both therapeutic treatmentand prophylactic or preventative measures, wherein the object is toprevent or slow down (lessen) an undesired physiological change ordisorder, such as the development or spread of cancer. For purposes ofthis invention, beneficial or desired clinical results include, but arenot limited to, alleviation of symptoms, diminishment of extent ofdisease, stabilized (i.e., not worsening) state of disease, delay orslowing of disease progression, amelioration or palliation of thedisease state, and remission (whether partial or total), whetherdetectable or undetectable. “Treatment” can also mean prolongingsurvival as compared to expected survival if not receiving treatment.Those in need of treatment include those already with the condition ordisorder as well as those prone to have the condition or disorder orthose in which the condition or disorder is to be prevented.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease, condition, or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease, condition, or disorder, or (iii) prevents or delays the onsetof one or more symptoms of the particular disease, condition, ordisorder described herein. In the case of cancer, the therapeuticallyeffective amount of the drug may reduce the number of cancer cells;reduce the tumor size; inhibit (i.e., slow to some extent and preferablystop) cancer cell infiltration into peripheral organs; inhibit (i.e.,slow to some extent and preferably stop) tumor metastasis; inhibit, tosome extent, tumor growth; and/or relieve to some extent one or more ofthe symptoms associated with the cancer. To the extent the drug mayprevent growth and/or kill existing cancer cells, it may be cytostaticand/or cytotoxic. For cancer therapy, efficacy can be measured, forexample, by assessing the time to disease progression (TTP) and/ordetermining the response rate (RR).

The terms “cancer” refers to or describe the physiological condition inmammals that is typically characterized by unregulated cell growth. A“tumor” comprises one or more cancerous cells. Examples of cancerinclude, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma,and leukemia or lymphoid malignancies. More particular examples of suchcancers include squamous cell cancer (e.g., epithelial squamous cellcancer), lung cancer including small-cell lung cancer, non-small celllung cancer (“NSCLC”), adenocarcinoma of the lung and squamous carcinomaof the lung, cancer of the peritoneum, hepatocellular cancer, gastric orstomach cancer including gastrointestinal cancer, pancreatic cancer,glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladdercancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectalcancer, endometrial or uterine carcinoma, salivary gland carcinoma,kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer,hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head andneck cancer.

A “chemotherapeutic agent” is a chemical compound useful in thetreatment of cancer, regardless of mechanism of action. Classes ofchemotherapeutic agents include, but are not limited to: alkylatingagents, antimetabolites, spindle poison plant alkaloids,cytotoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies,photosensitizers, and kinase inhibitors. Chemotherapeutic agents includecompounds used in “targeted therapy” and conventional chemotherapy.Examples of chemotherapeutic agents include: erlotinib (TARCEVA®,Genentech/OSI Pharm.), docetaxel (TAXOTERE®, Sanofi-Aventis), 5-FU(fluorouracil, 5-fluorouracil, CAS No. 51-21-8), gemcitabine (GEMZAR®,Lilly), PD-0325901 (CAS No. 391210-10-9, Pfizer), cisplatin(cis-diamine, dichloroplatinum(II), CAS No. 15663-27-1), carboplatin(CAS No. 41575-94-4), paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology,Princeton, N.J.), trastuzumab (HERCEPTIN®, Genentech), temozolomide(4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo [4.3.0]nona-2,7,9-triene-9-carboxamide, CAS No. 85622-93-1, TEMODAR®, TEMODAL®,Schering Plough), tamoxifen((Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethylethanamine,NOLVADEX®, ISTUBAL®, VALODEX®), and doxorubicin (ADRIAMYCIN®), Akti-1/2,HPPD, and rapamycin.

More examples of chemotherapeutic agents include: oxaliplatin(ELOXATIN®, Sanofi), bortezomib (VELCADE®, Millennium Pharm.), sutent(SUNITINIB®, SU11248, Pfizer), letrozole (FEMARA®, Novartis), imatinibmesylate (GLEEVEC®, Novartis), XL-518 (Mek inhibitor, Exelixis, WO2007/044515), ARRY-886 (Mek inhibitor, AZD6244, Array BioPharma, AstraZeneca), SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235(PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787/ZK222584 (Novartis), fulvestrant (FASLODEX®, AstraZeneca), leucovorin(folinic acid), rapamycin (sirolimus, RAPAMUNE®, Wyeth), lapatinib(TYKERB®, GSK572016, Glaxo Smith Kline), lonafarnib (SARASAR™, SCH66336, Schering Plough), sorafenib (NEXAVAR®, BAY43-9006, Bayer Labs),gefitinib (IRESSA®, AstraZeneca), irinotecan (CAMPTOSAR®, CPT-11,Pfizer), tipifarnib (ZARNESTRA™, Johnson & Johnson), ABRAXANE™(Cremophor-free), albumin-engineered nanoparticle formulations ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, Il),vandetanib (rINN, ZD6474, ZACTIMA®, AstraZeneca), chloranmbucil, AG1478,AG1571 (SU 5271; Sugen), temsirolimus (TORISEL®, Wyeth), pazopanib(GlaxoSmithKline), canfosfamide (TELCYTA®, Telik), thiotepa andcyclosphosphamide (CYTOXAN®, NEOSAR®); alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimethylomelamine; acetogenins(especially bullatacin and bullatacinone); a camptothecin (including thesynthetic analog topotecan); bryostatin; callystatin; CC-1065 (includingits adozelesin, carzelesin and bizelesin synthetic analogs);cryptophycins (particularly cryptophycin 1 and cryptophycin 8);dolastatin; duocarmycin (including the synthetic analogs, KW-2189 andCB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin;nitrogen mustards such as chlorambucil, chlornaphazine,chlorophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureassuch as carmustine, chlorozotocin, fotemustine, lomustine, nimustine,and ranimnustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, calicheamicin gamma1I, calicheamicin omegaI1 (Angew Chem.Intl. Ed. Engl. (1994) 33:183-186); dynemicin, dynemicin A;bisphosphonates, such as clodronate; an esperamicin; as well asneocarzinostatin chromophore and related chromoprotein enediyneantibiotic chromophores), aclacinomysins, actinomycin, authramycin,azaserine, bleomycins, cactinomycin, carabicin, caminomycin,carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin,6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin,cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin anddeoxydoxorubicin), epirubicin, esorubicin, idarubicin, nemorubicin,marcellomycin, mitomycins such as mitomycin C, mycophenolic acid,nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogs such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharidecomplex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin;sizofiran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; trichothecenes (especially T-2 toxin,verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; 6-thioguanine;mercaptopurine; methotrexate; platinum analogs such as cisplatin andcarboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone;vincristine; vinorelbine (NAVELBINE®); novantrone; teniposide;edatrexate; daunomycin; aminopterin; capecitabine (XELODA®, Roche);ibandronate; CPT-11; topoisomerase inhibitor RFS 2000;difluoromethylornithine (DMFO); retinoids such as retinoic acid; andpharmaceutically acceptable salts, acids and derivatives of any of theabove.

Also included in the definition of “chemotherapeutic agent” are: (i)anti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens and selective estrogen receptor modulators(SERMs), including, for example, tamoxifen (including NOLVADEX®;tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen,trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifinecitrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase,which regulates estrogen production in the adrenal glands, such as, forexample, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrolacetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole,RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX®(anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide,nilutamide, bicalutamide, leuprolide, and goserelin; as well astroxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) proteinkinase inhibitors such as MEK inhibitors (WO 2007/044515); (v) lipidkinase inhibitors; (vi) antisense oligonucleotides, particularly thosewhich inhibit expression of genes in signaling pathways implicated inaberrant cell proliferation, for example, PKC-alpha, Raf and H-Ras, suchas oblimersen (GENASENSE®, Genta Inc.); (vii) ribozymes such as VEGFexpression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors;(viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®,LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2; topoisomerase 1 inhibitorssuch as LURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such asbevacizumab (AVASTIN®, Genentech); and pharmaceutically acceptablesalts, acids and derivatives of any of the above.

Also included in the definition of “chemotherapeutic agent” aretherapeutic antibodies such as alemtuzumab (Campath), bevacizumab(AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab(VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec),pertuzumab (OMNITARG™, 2C4, Genentech), trastuzumab (HERCEPTIN®,Genentech), tositumomab (Bexxar, Corixia), and the antibody drugconjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth).

Humanized monoclonal antibodies with therapeutic potential aschemotherapeutic agents in combination with the PI3K inhibitors of theinvention include: alemtuzumab, apolizumab, aselizumab, atlizumab,bapineuzumab, bevacizumab, bivatuzumab mertansine, cantuzumabmertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab,daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab,fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab,labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab,motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab,ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab,pectuzumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab,reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab,sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan,tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab,trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab,urtoxazumab, and visilizumab.

A “metabolite” is a product produced through metabolism in the body of aspecified compound or salt thereof. Metabolites of a compound may beidentified using routine techniques known in the art and theiractivities determined using tests such as those described herein. Suchproducts may result for example from the oxidation, reduction,hydrolysis, amidation, deamidation, esterification, deesterification,enzymatic cleavage, and the like, of the administered compound.Accordingly, the invention includes metabolites of compounds of theinvention, including compounds produced by a process comprisingcontacting a Formula I compound of this invention with a mammal for aperiod of time sufficient to yield a metabolic product thereof.

The term “package insert” is used to refer to instructions customarilyincluded in commercial packages of therapeutic products, that containinformation about the indications, usage, dosage, administration,contraindications and/or warnings concerning the use of such therapeuticproducts.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds of the invention may contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand 1 or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or 1 meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer may also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which mayoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.For example, proton tautomers (also known as prototropic tautomers)include interconversions via migration of a proton, such as keto-enoland imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons.

The phrase “pharmaceutically acceptable salt” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a compound ofthe invention. Exemplary salts include, but are not limited, to sulfate,citrate, acetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate “mesylate”, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, and pamoate (i.e.,1,1′-methylene-bis(2-hydroxy-3-naphthoate)) salts. A pharmaceuticallyacceptable salt may involve the inclusion of another molecule such as anacetate ion, a succinate ion or other counter ion. The counter ion maybe any organic or inorganic moiety that stabilizes the charge on theparent compound. Furthermore, a pharmaceutically acceptable salt mayhave more than one charged atom in its structure. Instances wheremultiple charged atoms are part of the pharmaceutically acceptable saltcan have multiple counter ions. Hence, a pharmaceutically acceptablesalt can have one or more charged atoms and/or one or more counter ion.

If the compound of the invention is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an inorganic acid,such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,methanesulfonic acid, phosphoric acid and the like, or with an organicacid, such as acetic acid, trifluoroacetic acid, maleic acid, succinicacid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalicacid, glycolic acid, salicylic acid, a pyranosidyl acid, such asglucuronic acid or galacturonic acid, an alpha hydroxy acid, such ascitric acid or tartaric acid, an amino acid, such as aspartic acid orglutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid,a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid,or the like.

If the compound of the invention is an acid, the desiredpharmaceutically acceptable salt may be prepared by any suitable method,for example, treatment of the free acid with an inorganic or organicbase, such as an amine (primary, secondary or tertiary), an alkali metalhydroxide or alkaline earth metal hydroxide, or the like. Illustrativeexamples of suitable salts include, but are not limited to, organicsalts derived from amino acids, such as glycine and arginine, ammonia,primary, secondary, and tertiary amines, and cyclic amines, such aspiperidine, morpholine and piperazine, and inorganic salts derived fromsodium, calcium, potassium, magnesium, manganese, iron, copper, zinc,aluminum and lithium.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition must be compatible chemically and/or toxicologically, withthe other ingredients comprising a formulation, and/or the mammal beingtreated therewith.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the invention. Examples of solvents thatform solvates include, but are not limited to, water, isopropanol,ethanol, methanol, DMSO, ethylacetate, acetic acid, and ethanolamine.

The terms “compound of this invention,” and “compounds of the presentinvention” and “compounds of Formula I” include compounds of Formulas Iand stereoisomers, geometric isomers, tautomers, solvates, metabolites,and pharmaceutically acceptable salts and prodrugs thereof.

Any formula or structure given herein, including Formula I compounds, isalso intended to represent hydrates, solvates, and polymorphs of suchcompounds, and mixtures thereof.

Any formula or structure given herein, including Formula I compounds, isalso intended to represent unlabeled forms as well as isotopicallylabeled forms of the compounds. Isotopically labeled compounds havestructures depicted by the formulas given herein except that one or moreatoms are replaced by an atom having a selected atomic mass or massnumber. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, and chlorine, such as, but not limited to 2H(deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S,36Cl, and 125I. Various isotopically labeled compounds of the presentinvention, for example those into which radioactive isotopes such as 3H,13C, and 14C are incorporated. Such isotopically labelled compounds maybe useful in metabolic studies, reaction kinetic studies, detection orimaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. Deuterium labelled or substituted therapeutic compounds of theinvention may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism, and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements. An18F labeled compound may be useful for PET or SPECT studies.Isotopically labeled compounds of this invention and prodrugs thereofcan generally be prepared by carrying out the procedures disclosed inthe schemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent. Further, substitution with heavierisotopes, particularly deuterium (i.e., 2H or D) may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements or animprovement in therapeutic index. It is understood that deuterium inthis context is regarded as a substituent in the compound of the formula(I). The concentration of such a heavier isotope, specificallydeuterium, may be defined by an isotopic enrichment factor. In thecompounds of this invention any atom not specifically designated as aparticular isotope is meant to represent any stable isotope of thatatom. Unless otherwise stated, when a position is designatedspecifically as “H” or “hydrogen”, the position is understood to havehydrogen at its natural abundance isotopic composition. Accordingly, inthe compounds of this invention any atom specifically designated as adeuterium (D) is meant to represent deuterium.

Pyrazol-4-yl-heterocyclyl-carboxamide Compounds

The present invention provides pyrazol-4-yl-heterocyclyl-carboxamidecompounds of Formula I, including Formulas Ia, Ib, Ic and Id, andpharmaceutical formulations thereof, which are potentially useful in thetreatment of diseases, conditions and/or disorders modulated by Pimkinases.

and stereoisomers, geometric isomers, tautomers, or pharmaceuticallyacceptable salts thereof, wherein:

R¹ is H, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₆-C₂₀ aryl,C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, or C₁-C₂₀ heteroaryl;

R² is H, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, C₂-C₂₀heterocyclyl, C₁-C₂₀ heteroaryl, —(C₁-C₂₀ heteroaryl)-(C₂-C₂₀heterocyclyl), C₆-C₂₀ aryl, C₃-C₁₂ carbocyclyl, NR⁴R⁵ or OR⁴;

or R¹ and R² together form C₂-C₂₀ heterocyclyl or C₁-C₂₀ heteroaryl;

X is selected from the structures:

where the wavy line indicates the site of attachment;

R³ is H, Cl, Br, C₁-C₁₂ alkyl, —(C₁-C₁₂ alkylene)-(C₃-C₁₂ carbocyclyl),—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl), —(C₂-C₈ alkenylene)-(C₃-C₁₂carbocyclyl), —(C₂-C₈ alkenylene)-(C₂-C₂₀ heterocyclyl), C₆-C₂₀ aryl,—(C₆-C₂₀ arylene)-(C₂-C₂₀ heterocyclyl), —(C₆-C₂₀ arylene)-(C₁-C₁₂alkylene)-(C₂-C₂₀ heterocyclyl), C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, or C₁-C₂₀ heteroaryl;

R⁴ and R⁵ are independently selected from H, C₁-C₁₂ alkyl, C₆-C₂₀ aryl,C₃-C₁₂ carbocyclyl, C₂-C₂₀ heterocyclyl, C₁-C₂₀ heteroaryl, —(C₁-C₁₂alkylene)-(C₆-C₂₀ aryl), —(C₁-C₁₂ alkylene)-(C₃-C₁₂ carbocyclyl),—(C₁-C₁₂ alkylene)-(C₂-C₂₀ heterocyclyl), —(C₁-C₁₂ alkylene)-(C₁-C₂₀heteroaryl); or R⁴ and R⁵ together form C₂-C₂₀ heterocyclyl or C₁-C₂₀heteroaryl;

R⁶ is H or —NH₂;

R⁷ is H, F, CH₂F, CHF₂, and CF₃; and

where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl,aryl, and heteroaryl are optionally substituted with one or more groupsindependently selected from F, Cl, Br, I, —CH₃, —CH₂CH₃, —CH(CH₃)₂,—CH₂CH(CH₃)₂, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CHCH₂NH₂, —CH₂CH(CH₃)NH₂, —CH₂OH,—CH₂CH₂OH, —C(CH₃)₂OH, —CH(OH)CH(CH₃)₂, —C(CH₃)₂CH₂OH, —CH₂CH₂SO₂CH₃,—CN, —CF₃, —CO₂H, —COCH₃, —CO₂CH₃, —CO₂C(CH₃)₃, —COCH(OH)CH₃, —CONH₂,—CONHCH₃, —CON(CH₃)₂, —C(CH₃)₂CONH₂, —NO₂, —NH₂, —NHCH₃, —N(CH₃)₂,—NHCOCH₃, —N(CH₃)COCH₃, —NHS(O)₂CH₃, —N(CH₃)C(CH₃)₂CONH₂,—N(CH₃)CH₂CH₂S(O)₂CH₃, ═O, —OH, —OCH₃, —S(O)₂N(CH₃)₂, —SCH₃, —CH₂OCH₃,—S(O)₂CH₃, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, piperazinyl,piperidinyl, (piperidin-4-yl)ethyl), pyranyl, (piperidin-4-ylmethyl),morpholinomethyl, and morpholino.

Exemplary embodiments of Formula I compounds include wherein R¹ isC₁-C₁₂ alkyl.

Exemplary embodiments of Formula I compounds include wherein R² is NR⁴R⁵and together form C₂-C₂₀ heterocyclyl or C₁-C₂₀ heteroaryl.

Exemplary embodiments of Formula I compounds include wherein R² isselected from the structures:

where the wavy line indicates the site of attachment.

Exemplary embodiments of Formula I compounds include wherein R² isselected from the structures:

where the wavy line indicates the site of attachment.

Exemplary embodiments of Formula I compounds include wherein R² is OR⁴.

Exemplary embodiments of Formula I compounds include wherein R² isselected from the structures:

where the wavy line indicates the site of attachment.

Exemplary embodiments of Formula I compounds include wherein R¹ and R²together form C₂-C₂₀ heterocyclyl or C₁-C₂₀ heteroaryl selected from thestructures:

where the C₂-C₂₀ heterocyclyl or C₁-C₂₀ heteroaryl formed by R¹ and R²is optionally substituted with one or more groups independently selectedfrom F, Cl, Br, I, —CH₃, —CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂NH₂, —CH₂CH₂NH₂,—CH₂CH(CH₃)NH₂, —CH₂OH, —CH₂CH₂OH, —C(CH₃)₂OH, —CH(OH)CH(CH₃)₂,—C(CH₃)₂CH₂OH, —CH₂CH₂SO₂CH₃, —CN, —CF₃, —CO₂H, —COCH₃, —CO₂CH₃,—CO₂C(CH₃)₃, —COCH(OH)CH₃, —CONH₂, CONHCH₃, —CON(CH₃)₂, —C(CH₃)₂CONH₂,—NO₂, —NH₂, —NHCH₃, —N(CH₃)₂, —NHCOCH₃, —N(CH₃)COCH₃, —NHS(O)₂CH₃,—N(CH₃)C(CH₃)₂CONH₂, —N(CH₃)CH₂CH₂S(O)₂CH₃, ═O, —OH, —OCH₃,—S(O)₂N(CH₃)₂, —SCH₃, —CH₂OCH₃, —S(O)₂CH₃, cyclopropyl, azetidinyl,oxetanyl, pyrrolidinyl, and morpholino.

Exemplary embodiments of Formula I compounds include wherein R³ isC₆-C₂₀ aryl, including where phenyl substituted with one or more F.

Exemplary embodiments of Formula I compounds include the structures ofFormula Ia, Ib, Ic, and Id:

Where R¹ is H, it will be understood that Formula I compounds includepyrazole tautomers, such as:

Biological Evaluation

Determination of the Pim kinase activity of a Formula I compound ispossible by a number of direct and indirect detection methods. Certainexemplary compounds described herein were assayed for their Pim kinasebinding activity, including isoforms Pim-1, Pim-2, and Pim-3, (Example901) and in vitro activity against tumor cells (Example 902). Certainexemplary compounds of the invention had Pim binding activity IC₅₀values less than about 1 micromolar (μM). Certain compounds of theinvention had tumor cell-based activity EC₅₀ values less than about 1micromolar (μM).

Exemplary Formula I compounds in Table 1 and Table 2 were made,characterized, and tested for inhibition of Pim kinase according to themethods of this invention, and have the following structures andcorresponding names (ChemBioDraw Ultra, Version 11.0, CambridgeSoftCorp., Cambridge Mass.).

TABLE 1 No. Structure Name 101

5-amino-2-(2,6-difluorophenyl)-N- (1H-pyrazol-4-yl)thiazole-4-carboxamide 102

5-amino-2-(2,6-difluorophenyl)-N-(1- methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide 103

(S)-5-amino-N-(5-(3-aminopiperidin- 1-yl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 104

5-amino-2-(2-fluorophenyl)-N-(1- methyl-5-(piperidin-4-ylmethylamino-1H-pyrazol-4- yl)thiazole-4-carboxamide 105

5-amino-2-(2,6-difluorophenyl)-N-(1- methyl-5-(piperidin-4-ylmethylamino)-1H-pyrazol-4- yl)thiazole-4-carboxamide 106

(S)-5-amino-N-(5-(3-aminopiperidin- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 107

(S)-5-amino-N-(5-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide 108

5-amino-N-(5-(4-aminopiperidin-1- yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 109

3-amino-N-(5-(4-aminopiperidin-1- yl)-1-methyl-1H-pyrazol-4-yl)-6-phenylpicolinamide 110

3-amino-N-(5-(4-aminopiperidin-1- yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide 111

(S)-3-amino-N-(5-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2- fluorophenyl)picolinamide 112

(R)-3-amino-N-(5-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2- fluorophenyl)picolinamide 113

5-amino-N-(5-(4-aminoazepan-1-yl)- 1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 114

3-amino-N-(5-(4-aminoazepan-1-yl)- 1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide 115

5-amino-2-(2,6-difluorophenyl)-N-(1- methyl-5-(piperidin-4-ylmethoxy)-1H-pyrazol-4-yl)thiazole-4- carboxamide 116

3-amino-6-(2-fluorophenyl)-N-(1- methyl-5-(piperidin-4-yloxy)-1H-pyrazol-4-yl)picolinamide 117

3-amino-6-(2-fluorophenyl)-N-(1- methyl-5-(piperidin-4-ylmethoxy)-1H-pyrazol-4-yl)picolinamide 118

3-amino-N-(5-(4-aminopiperidin-1- yl)-1-methyl-1H-pyrazol-4-yl)-6-bromopyrazine-2-carboxamide 119

(S)-3-amino-N-(5-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide 120

5-amino-2-(2,6-difluorophenyl)-N-(1- methyl-5-(piperidin-4-yloxy)-1H-pyrazol-4-yl)thiazole-4-carboxamide 121

(S)-3-amino-N-(5-(3-aminopiperidin- 1-yl)-1-methyl-1H-pyrazol-4-yl)-6-bromopyrazine-2-carboxamide 122

3-amino-N-(5-(4-aminopiperidin-1- yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide 123

(S)-3-amino-N-(5-(3-aminopiperidin- 1-yl)-1-methyl-1H-pyrazol-4-yl)-6-chloropyrazine-2-carboxamide 124

(R)-3-amino-N-(5-(3- aminopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2- fluorophenyl)picolinamide 125

(S)-3-amino-N-(5-(3-aminopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2- fluorophenyl)picolinamide 126

(R)-5-amino-N-(5-(3- aminopyrrolidin-1-yl)-1-methyl-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide 127

(S)-5-amino-N-(5-(3-aminopyrrolidin- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 128

(S)-3-amino-N-(5-(3- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2- fluorophenyl)picolinamide 129

(R)-3-amino-N-(5-(3- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2- fluorophenyl)picolinamide 130

3-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2- fluorophenyl)picolinamide 131

(S)-5-amino-N-(5-(3- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide132

(R)-5-amino-N-(5-(3- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide133

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide134

(S)-3-amino-N-(5-(3- (aminomethyl)pyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2- fluorophenyl)picolinamide 135

(R)-5-amino-N-(5-(3- (aminomethyl)pyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide136

(R)-3-amino-N-(5-(3- (aminomethyl)pyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2- fluorophenyl)picolinamide 137

(S)-5-amino-N-(5-(3- (aminomethyl)pyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide138

5-amino-2-(2,6-difluorophenyl)-N-(1- (oxetan-3-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 139

(S)-5-amino-N-(5-(4-aminoazepan-1- yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 140

(R)-5-amino-N-(5-(4-aminoazepan-1- yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 141

(R)-3-amino-N-(5-(4-aminoazepan-1- yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide 142

(S)-3-amino-N-(5-(4-aminoazepan-1- yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide 143

(S)-3-amino-N-(5-(4-aminoazepan-1- yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide 144

(R)-5-amino-N-(5-(3-aminopiperidin- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 145

(R)-3-amino-N-(5-(4-aminoazepan-1- yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide 146

(R)-N-(5-(3-(aminomethyl)piperidin- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 147

(R)-benzyl 1-(4-(5-amino-2-(2,6- difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol- 5-yl)azepan-4-ylcarbamate 148

(R)-N-(5-(4-aminoazepan-1-yl)-1- methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 149

(S)-N-(5-(4-aminoazepan-1-yl)-1- methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 150

5-amino-N-(5-(6-amino-3- azabicyclo[3.1.0]hexan-3-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide151

3-amino-N-(5-(6-amino-3- azabicyclo[3.1.0]hexan-3-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2- fluorophenyl)picolinamide 152

3-amino-N-(5-(4-aminopiperidin-1- yl)-1-methyl-1H-pyrazol-4-yl)-6-chloropyrazine-2-carboxamide 153

N-(3-(6-(4-aminopiperidin-1- yl)yridine-2-yl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide 154

5-amino-2-(2,6-difluorophenyl)-N-(1- methyl-5-o-tolyl-1H-pyrazol-4-yl)thiazole-4-carboxamide 155

3-amino-6-(2-fluorophenyl)-N-(1- methyl-5-o-tolyl-1H-pyrazol-4-yl)picolinamide 156

3-amino-N-(5-(3-aminophenyl)-1- methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide 157

5-amino-N-(5-(3-aminophenyl)-1- methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide

TABLE 2 No. Structure Name 158

(S)-3-amino-N-(5-(3-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide 159

(R)-5-amino-N-(5-(3-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 160

(R)-3-amino-N-(5-(3-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide 161

(S)-5-amino-N-(5-(3-aminoazepan 1-yl)-1-methyl-1H-pyrazol-4-yl)-2(2,6-difluorophenyl)thiazole-4- carboxamide 162

5-amino-2-(2,6-difluorophenyl)-N- (1-methyl-5-(piperazin-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 163

3-amino-6-(2-fluorophenyl)-N-(1- methyl-5-(piperazin-1-yl)-1H-pyrazol-4-yl)picolinamide 164

N-(5-(1,4-diazepan-1-yl)-1-methyl- 1H-pyrazol-4-yl)-5-amino-2-(2,6-difluorophenyl)thiazole-4- carboxamide 165

5-amino-2-(2,6-difluorophenyl)-N- (1-ethyl-1H-pyrazol-4-yl)thiazole-4-carboxamide 166

N-(3-(piperidin-1-yl)-1H-pyrazol-4- yl)pyrazine-2-carboxamide 167

N-(3-(4-aminopiperidin-1-yl)-1H- pyrazol-4-yl(pyrazine-2- carboxamide168

5-amino-2-(2,6-difluorophenyl)-N- (1-methyl-5-(1H-pyrrolo[3,4-c]pyridin- 2(3H,3aH,4H,5H,6H,7H,7aH)-yl)- 1H-pyrazol-4-yl)thiazole-4-carboxamide 169

5-amino-2-(2-fluorophenyl)-N-(1- methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide 170

5-amino-2-(2-fluorophenyl)-N-(1- (piperidin-4-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 171

N-(3-(4-(aminomethyl)piperidin-1- yl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide 172

5-amino-2-(2,6-difluorophenyl)-N- (1-(piperidin-4-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 173

5-amino-N-(1-ethyl-1H-pyrazol-4- yl)-2-(2-fluorophenyl)thiazole-4-carboxamide 174

5-amino-2-(2-fluorophenyl)-N-(1- isopropyl-1H-pyrazol-4-yl)thiazole-4-carboxamide 175

5-amino-2-(2,6-difluorophenyl)-N- (1-isopropyl-1H-pyrazol-4-yl)thiazole-4-carboxamide 176

5-amino-2-(2,6-difluorophenyl)-N- (1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 177

5-amino-2-(2-fluorophenyl)-N-(1- (pyrrolidin-3-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 178

5-amino-N-(1-(cyclopropylmethyl)- 1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4- carboxamide 179

5-amino-N-(1-(cyclopropylmethyl)- 1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 180

(R)-5-amino-2-(2,6-difluorophenyl)- N-(1-(piperidin-3-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 181

N-(5-(3-(aminomethyl)piperidin-1- yl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide 182

(S)-5-amino-2-(2,6-difluorophenyl)- N-(1-(piperidin-3-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 183

5-amino-2-(2,6-difluorophenyl)-N- (1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 184

5-amino-2-(2,6-difluorophenyl)-N- (1,5-dimethyl-1H-pyrazol-4-yl)thiazole-4-carboxamide 185

N-(5-(4-aminopiperidin-1-yl)-1- methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2- carboxamide 186

5-amino-2-(2,6-difluorophenyl)-N- (4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)thiazole-4- carboxamide 187

N-(5-(1,4-diazepan-1-yl)-1-methyl- 1H-pyrazol-4-yl)-3-amino-6-(2-fluorophenyl)picolinamide 188

N-(3-(4-aminopiperidin-1-yl)-1H- pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2- carboxamide 189

5-amino-2-(2,6-difluorophenyl)-N- (5-(4-hydroxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide 190

(R)-N-(5-(3-aminopiperidin-1-yl)-1- methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2- carboxamide 191

(S)-N-(5-(3-aminopiperidin-1-yl)-1- methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2- carboxamide 192

N-(5-(4-(aminomethyl)piperidin-1- yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2- carboxamide 193

N-(5-(4-(2-aminoethyl)piperidin-1- yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2- carboxamide 194

N-(5-(1,4-diazepan-1-yl)-1-methyl- 1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2- carboxamide 195

(R)-N-(5-(3-aminoazepan-1-yl)-1- methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2- carboxamide 196

(S)-N-(5-(3-aminoazepan-1-yl)-1- methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2- carboxamide 197

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4- carboxamide 198

N-(5-(4-aminopiperidin-1-yl)-1- methyl-1H-pyrazol-4-yl)-5-(2-fluorophenyl)nicotinamide 199

5-amino-2-(2,6-difluorophenyl)-N- (5-(4-(dimethylamino)azepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole- 4-carboxamide 200

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,4-difluorophenyl)thiazole-4- carboxamide 201

5-amino-N-(5-(4-(2- aminoethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide202

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluoro-4- methoxyphenyl)thiazole-4- carboxamide 203

5-amino-2-(2,6-difluorophenyl)-N- (1-methyl-5-(4-(N-methylacetamido)azepan-1-yl)-1H- pyrazol-4-yl)thiazole-4-carboxamide 204

5-amino-N-(1-(difluoromethyl)-1H- pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 205

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-(trifluoromethyl)phenyl)thiazole- 4-carboxamide 206

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(4-(trifluoromethyl)phenyl)thiazole- 4-carboxamide 207

N-(1H-pyrazol-4-yl)pyrazine-2- carboxamide 208

(R)-5-amino-2-(2,6-difluorophenyl)- N-(1-methyl-5-(4-(N-methylacetamido)azepan-1-yl)-1H- pyrazol-4-yl)thiazole-4-carboxamide 209

5-amino-N-(1-(2-aminoethyl)-1H- pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 210

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-(trifluoromethyl)phenyl)thiazole- 4-carboxamide 211

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-4-methylphenyl)thiazole- 4-carboxamide 212

(R)-N-(5-(4-aminoazepan-1-yl)-1- methyl-1H-pyrazol-4-yl)-5-fluoro-6-(2-fluorophenyl)picolinamide 213

N-(3-methyl-1H-pyrazol-4- yl)pyrazine-2-carboxamide 214

5-amino-2-(2,6-difluorophenyl)-N- (1-(2-(piperidin-1-yl)ethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 215

5-amino-2-(2,6-difluorophenyl)-N- (1-(2-morpholinoethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 216

(R)-5-amino-N-(5-(3-(2- aminoethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide217

(S)-5-amino-2-(2,6-difluorophenyl)- N-(1-methyl-5-(2-(pyrrolidin-2-yl)ethylamino)-1H-pyrazol-4- yl)thiazole-4-carboxamide 218

5-amino-N-(5-(azepan-1-yl)-1- methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 219

(R)-N-(5-(4-aminoazepan-1-yl)-1- methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2- carboxamide 220

(S)-N-(5-(4-aminoazepan-1-yl)-1- methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2- carboxamide 221

(R)-5-amino-2-(2,6-difluorophenyl)- N-(1-methyl-5-(2-(pyrrolidin-2-yl)ethylamino)-1H-pyrazol-4- yl)thiazole-4-carboxamide 222

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(4-cyclopropyl-2- fluorophenyl)thiazole-4- carboxamide 223

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole- 4-carboxamide 224

(S)-5-amino-2-(2,6-difluorophenyl)- N-(5-(4-(dimethylamino)azepan-1-yl)-1-methyl-1H-pyrazol-4- yl)thiazole-4-carboxamide 225

(R)-5-amino-2-(2,6-difluorophenyl)- N-(5-(4-(dimethylamino)azepan-1-yl)-1-methyl-1H-pyrazol-4- yl)thiazole-4-carboxamide 226

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4- carboxamide 227

(R)-N-(5-(4-acetamidoazepan-1-yl)- 1-methyl-1H-pyrazol-4-yl)-5-amino-2-(2,6-difluorophenyl)thiazole-4- carboxamide 228

5-amino-N-(5-(3-(2- aminoethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide229

(R)-N-(5-(4-aminoazepan-1-yl)-1- methyl-1H-pyrazol-4-yl)-5-fluoro-6-phenylpicolinamide 230

5-amino-2-(2,6-difluorophenyl)-N- (1-methyl-5-((tetrahydro-2H-pyran-4-yl)methoxy)-1H-pyrazol-4- yl)thiazole-4-carboxamide 231

5-amino-2-(2,6-difluorophenyl)-N- (1-methyl-5-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)thiazole-4- carboxamide 232

(R)-5-amino-2-(2,6-difluorophenyl)- N-(1-methyl-5-(tetrahydrofuran-3-yloxy)-1H-pyrazol-4-yl)thiazole-4- carboxamide 233

(S)-5-amino-2-(2,6-difluorophenyl)- N-(1-methyl-5-(tetrahydrofuran-3-yloxy)-1H-pyrazol-4-yl)thiazole-4- carboxamide 234

(R)-N-(5-(4-aminoazepan-1-yl)-1- methyl-1H-pyrazol-4-yl)-6-cyclopentyl-5-fluoropicolinamide 235

(R)-N-(5-(4-aminoazepan-1-yl)-1- methyl-1H-pyrazol-4-yl)-6-(5-(dimethylcarbamoyl)-2- fluorophenyl)-5-fluoropicolinamide 236

(R)-N-(5-(4-aminoazepan-1-yl)-1- methyl-1H-pyrazol-4-yl)-6-cyclopentenyl-5-fluoropicolinamide 237

(R)-N-(5-(4-aminoazepan-1-yl)-1- methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)picolinamide 238

(R)-N-(5-(4-aminoazepan-1-yl)-1- methyl-1H-pyrazol-4-yl)-6-(2,6-difluorophenyl)-5- fluoropicolinamide 239

5-amino-2-(2,6-difluorophenyl)-N- (1-methyl-5-morpholino-1H-pyrazol-4-yl)thiazole-4-carboxamide 240

(R)-5-amino-2-(2,6-difluorophenyl)- N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide 241

5-amino-N-(5-(4-aminoazepan-1- yl)-1-ethyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 242

(S)-5-amino-2-(2,6-difluorophenyl)- N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide 243

5-amino-2-(2,6-difluorophenyl)-N- (1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)thiazole-4- carboxamide 244

5-amino-N-(1-methyl-1H-pyrazol-4- yl)-2-(3-morpholinophenyl)thiazole-4-carboxamide 245

5-amino-2-(2,6-difluorophenyl)-N- (5-(4-fluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide 246

5-amino-2-(2,6-difluorophenyl)-N- (5-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide 247

(S)-5-amino-2-(2,6-difluorophenyl)- N-(5-(3-fluoropyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide 248

(R)-5-amino-2-(2,6-difluorophenyl)- N-(5-(3-fluoropyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide 249

5-amino-2-(2,6-difluorophenyl)-N- (1-methyl-5-(piperidin-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 250

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3- cyanophenyl)thiazole-4- carboxamide 251

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3- fluorophenyl)thiazole-4- carboxamide 252

5-amino-N-(5-(3-(2- aminoethyl)pyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide253

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-5- (trifluoromethyl)phenyl)thiazole-4- carboxamide 254

N-(5-((1S,4S)-2,5- diazabicyclo[2.2.l]heptan-2-yl)-1-methyl-1H-pyrazol-4-yl)-5-amino-2- (2,6-difluorophenyl)thiazole-4-carboxamide 255

5-amino-2-(2,6-difluorophenyl)-N- (1-methyl-5-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 256

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2- cyclopentenylthiazole-4- carboxamide 257

(E)-5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2- cyclohexylvinyl)thiazole-4- carboxamide258

5-amino-2-(2,6-difluorophenyl)-N- (1-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazol- 4-yl)thiazole-4-carboxamide 259

5-amino-2-(2,6-difluorophenyl)-N- (5-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-1-methyl- 1H-pyrazol-4-yl)thiazole-4-carboxamide 260

5-amino-2-(2,6-difluorophenyl)-N- (1-methyl-5-((tetrahydro-2H-pyran-4-yl)methylamino)-1H-pyrazol-4- yl)thiazole-4-carboxamide 261

5-amino-2-(2,6-difluorophenyl)-N- (5-(dimethylamino)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide 262

5-amino-N-(5-(cyclohexyloxy)-1- methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 263

5-amino-2-(2,6-difluorophenyl)-N- (1-methyl-5-(piperidin-4-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 264

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-(cyclopropylmethyl)-1H-pyrazol-4- yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide 265

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2- cyclohexenylthiazole-4-carboxamide 266

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2- cycloheptenylthiazole-4- carboxamide 267

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3- ethylphenyl)thiazole-4-carboxamide 268

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3- methoxyphenyl)thiazole-4- carboxamide 269

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2- isopropylphenyl)thiazole-4- carboxamide270

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-isopropyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4-carboxamide 271

5-amino-2-(2,6-difluorophenyl)-N- (5-((2- hydroxyethyl)(methyl)amino)-1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide 272

(S)-5-amino-2-(2,6-difluorophenyl)- N-(1-methyl-5-(piperidin-3-yloxy)-1H-pyrazol-4-yl)thiazole-4- carboxamide 273

(R)-5-amino-2-(3-(3- (aminomethyl)pyrrolidin-1-yl)phenyl)-N-(1-methyl-1H-pyrazol- 4-yl)thiazole-4-carboxamide 274

5-amino-N-(1-methyl-1H-pyrazol-4- yl)-2-(3-(piperazin-1-yl)phenyl)thiazole-4-carboxamide 275

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2- carbamoylphenyl)thiazole-4- carboxamide276

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3- (dimethylamino)phenyl)thiazole-4-carboxamide 277

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,5- dichlorophenyl)thiazole-4- carboxamide278

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(4- hydroxy-2-(trifluoromethyl)phenyl)thiazole-4- carboxamide 279

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5- fluoro-2-(trifluoromethyl)phenyl)thiazole-4- carboxamide 280

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(4- methoxy-2-(trifluoromethyl)phenyl)thiazole-4- carboxamide 281

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2- cyclohexylethyl)thiazole-4- carboxamide282

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2- cyclohexylthiazole-4-carboxamide 283

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide 284

(R)-5-amino-2-(2,6-difluorophenyl)- N-(1-methyl-5-(piperidin-3-yloxy)-1H-pyrazol-4-yl)thiazole-4- carboxamide 285

5-amino-2-(3-(4- (aminomethyl)piperidin-1-yl)phenyl)-N-(1-methyl-1H-pyrazol- 4-yl)thiazole-4-carboxamide 286

5-amino-N-(5-(4,4-difluoroazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 287

5-amino-2-(2,6-difluorophenyl)-N- (5-(3,3-difluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide 288

5-amino-2-(2,6-difluorophenyl)-N- (1-methyl-5-(3-oxopiperazin-1-yl)-1H-pyrazol-4-yl)thiazole-4- carboxamide 289

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2- cyclopentylthiazole-4-carboxamide 290

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2- (tetrahydro-2H-pyran-2-yl)thiazole-4-carboxamide 291

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-cyclopropyl-2-fluoro-3- methylphenyl)thiazole-4- carboxamide 292

(R)-N-(5-(4-aminoazepan-1-yl)-1- methyl-1H-pyrazol-4-yl)-6-bromopicolinamide 293

(R)-N-(5-(4-aminoazepan-1-yl)-1- methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide 294

5-amino-2-(2,6-difluorophenyl)-N- (1-methyl-5-(3-oxo-1,4-diazepan-1-yl)-1H-pyrazol-4-yl)thiazole-4- carboxamide 295

5-amino-2-(2,6-difluorophenyl)-N- (5-(3-fluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide 296

5-amino-2-(2,6-difluorophenyl)-N- (1-methyl-5-(4-methylpiperazin-1-yl)-1H-pyrazol-4-yl)thiazole-4- carboxamide 297

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5- fluoro-2-hydroxyphenyl)thiazole-4-carboxamide 298

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5- cyano-2-fluorophenyl)thiazole-4-carboxamide 299

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2- cycloheptylthiazole-4-carboxamide 300

5-amino-N-(5-(4-cyanopiperidin-1- yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 301

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3- isopropylphenyl)thiazole-4- carboxamide302

(R)-3-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)picolinamide 303

(R)-N-(5-(4-aminoazepan-1-yl)-1- methyl-1H-pyrazol-4-yl)-5-fluoropicolinamide 304

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2- cyclopropylthiazole-4-carboxamide 305

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2- cyclobutylthiazole-4-carboxamide 306

5-amino-2-(2,6-difluorophenyl)-N- (1-methyl-5-(piperidin-4-ylamino)-1H-pyrazol-4-yl)thiazole-4- carboxamide 307

5-amino-2-(2,6-difluorophenyl)-N- (2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)thiazole-4- carboxamide 308

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-bromo-2-fluorophenyl)thiazole-4- carboxamide 309

(R)-N-(5-(4-aminoazepan-1-yl)-1- methyl-1H-pyrazol-4- yl)picolinamide310

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-isopropyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 311

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-cyclopropyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 312

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide 313

(S)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-ethyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 314

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5- chloro-2-fluorophenyl)thiazole-4-carboxamide 315

(S)-5-amino-2-(3-(3- (aminomethyl)pyrrolidin-1-yl)phenyl)-N-(1-methyl-1H-pyrazol- 4-yl)thiazole-4-carboxamide 316

5-amino-2-(3-(3-aminopyrrolidin-1- yl)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide 317

3-amino-6-bromo-N-(1-methyl-1H- pyrazol-4-yl)picolinamide 318

3-amino-N-(1-methyl-1H-pyrazol-4- yl)-6-(3-(piperidin-1-yl)phenyl)picolinamide 319

5-amino-2-(2,6-difluorophenyl)-N- (1-methyl-5-(1,4-oxazepan-4-yl)-1H-pyrazol-4-yl)thiazole-4- carboxamide 320

5-amino-2-(2,6-difluorophenyl)-N- (1-methyl-5-(5-oxo-1,4-diazepan-1-yl)-1H-pyrazol-4-yl)thiazole-4- carboxamide 321

5-amino-2-(2,6-difluorophenyl)-N- (5-(4-(2-hydroxyethyl)piperazin-1-yl)-1-methyl-1H-pyrazol-4- yl)thiazole-4-carboxamide 322

(S)-5-amino-2-(3-(3- hydroxypyrrolidin-1-yl)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)thiazole- 4-carboxamide 323

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-fluorophenyl)thiazole-4- carboxamide 324

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-fluorophenyl)thiazole-4- carboxamide 325

3-amino-N-(1-methyl-1H-pyrazol-4- yl)-6-(3-morpholinophenyl)picolinamide 326

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carboxamide 327

(R)-5-amino-2-(2,6-difluorophenyl)- N-(1-methyl-5-(4-(methylamino)azepan-1-yl)-1H- pyrazol-4-yl)thiazole-4-carboxamide 328

(S)-5-amino-2-(2,6-difluorophenyl)- N-(1-methyl-5-(4-(methylamino)azepan-1-yl)-1H- pyrazol-4-yl)thiazole-4-carboxamide 329

3-amino-N-(1-methyl-1H-pyrazol-4- yl)-6-(3-(pyrrolidin-1-yl)phenyl)picolinamide 330

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)pyrimidine-4- carboxamide 331

3-amino-N-(1-methyl-1H-pyrazol-4- yl)-6-(3-(piperazin-1-yl)phenyl)picolinamide 332

(R)-5-amino-N-(5-(azepan-4- ylamino)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 333

5-amino-2-(2,6-difluorophenyl)-N- (1-(2-(piperidin-4-yl)ethyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazol- 7-yl)thiazole-4-carboxamide 334

5-amino-2-(2,6-difluorophenyl)-N- (5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol- 2(1H)-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide 335

5-amino-2-(2,6-difluorophenyl)-N- (1-methyl-5-(methyl(piperidin-4-yl)amino)-1H-pyrazol-4-yl)thiazole- 4-carboxamide 336

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-ethyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 337

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cyclopentenylthiazole-4- carboxamide 338

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cyclohexenylthiazole-4-carboxamide 339

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cycloheptenylthiazole-4- carboxamide 340

5-amino-N-(5-((1s,4s)-4- aminocyclohexylamino)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide 341

(S)-3-amino-6-(3-(3-aminopiperidin- 1-yl)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)picolinamide 342

(S)-3-amino-6-(3-(3- aminopyrrolidin-1-yl)phenyl)-N-(1-methyl-1H-pyrazol-4- yl)picolinamide 343

(R)-3-amino-6-(3-(3- aminopiperidin-1-yl)phenyl)-N-(1-methyl-1H-pyrazol-4- yl)picolinamide 344

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-methylthiazole-4-carboxamide 345

(R)-3-amino-6-(3-(3- aminopyrrolidin-1-yl)phenyl)-N-(1-methyl-1H-pyrazol-4- yl)picolinamide 346

5-amino-N-(5-((cis-3- aminocyclohexylamino)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide 347

5-amino-2-(2,6-difluorophenyl)-N- (5-(4-(2,4-dimethoxybenzylamino)cyclohexyl)- 1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide 348

5-amino-2-(2,6-difluorophenyl)-N- (1-(piperidin-4-ylmethyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazol- 7-yl)thiazole-4-carboxamide 349

5-amino-N-(5-(3- aminopropylamino)-1-methyl-1H- pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 350

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,5-dichlorophenyl)thiazole-4- carboxamide 351

5-amino-N-(5-(5-amino-4,4- difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide 352

5-amino-N-(5-((3- aminopropyl)(methyl)amino)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide353

5-amino-2-(2,6-difluorophenyl)-N- (1-(2-fluoroethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 354

5-amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluoro-3-methoxyphenyl)thiazole-4-carboxamide 355

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-cyanophenyl)thiazole-4- carboxamide 356

5-amino-N-(1-methyl-1H-pyrazol-4- yl)-2-(3-(morpholinomethyl)phenyl)thiazole- 4-carboxamide 357

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-fluoro-2-hydroxyphenyl)thiazole- 4-carboxamide 358

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-cyano-2-fluorophenyl)thiazole-4- carboxamide 359

(S)-N-(5-(4-aminoazepan-1-yl)-1- methyl-1H-pyrazol-4-yl)-5-fluoro-6-(2-fluorophenyl)picolinamide 360

5-amino-N-(5-((1r,4r)-4- aminocyclohexylamino)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide 361

5-amino-2-(2,6-difluorophenyl)-N- (5-(4-hydroxycyclohexyl)-1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide 362

5-amino-N-(5-((trans-3- aminocyclohexylamino)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide 363

5-amino-N-(1-benzyl-1H-pyrazol-4- yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide 364

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-ethyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4- carboxamide 365

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-cyclopropyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4- carboxamide 366

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-2-(2- fluorophenyl)thiazole-4- carboxamide 367

5-amino-N-(1-(3-aminopropyl)-2,3- dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)-2-(2,6-difluorophenyl)thiazole- 4-carboxamide 368

(S)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)pyrimidine-4- carboxamide 369

5-amino-N-(5-(4-aminocyclohexyl)- 1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 370

(S)-5-amino-N-(5-(azepan-4- ylamino)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 371

5-amino-N-(5-(2- (aminomethyl)morpholino)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide372

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-chloro-2-fluorophenyl)thiazole-4- carboxamide 373

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-bromo-2-fluorophenyl)thiazole-4- carboxamide 374

(S)-5-amino-2-(2,6-difluorophenyl)- N-(5-(4-hydroxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide 375

(R)-5-amino-2-(2,6-difluorophenyl)- N-(5-(4-hydroxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide 376

5-amino-N-(5-(4-hydroxyazepan-1- yl)-1-methyl-1H-pyrazol-4-yl)-2-(pyridin-2-yl)thiazole-4- carboxamide 377

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,3-difluorophenyl)thiazole-4- carboxamide 378

5-amino-N-(5-(trans-3- aminocyclohexyl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide 379

5-amino-N-(5-(cis-3- aminocyclohexyl)-1-methyl-1H- pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 380

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(pyridin-2-yl)thiazole-4- carboxamide 381

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-3-methylphenyl)thiazole- 4-carboxamide 382

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-cyclopropyl-2- fluorophenyl)thiazole-4- carboxamide 383

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-ethyl-2-fluorophenyl)thiazole-4- carboxamide 384

5-amino-N-(1-(2,2-difluoroethyl)- 1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 385

5-amino-2-(2,6-difluorophenyl)-N- (1-propyl-1H-pyrazol-4-yl)thiazole-4-carboxamide 386

5-amino-2-(2,6-difluorophenyl)-N- (1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 387

N-(5-(1,4-diazepan-1-yl)-1-methyl- 1H-pyrazol-4-yl)-3-amino-6-(2-fluorophenyl)picolinamide 388

3-amino-6-(2-fluorophenyl)-N-(1- methyl-5-(1H-pyrrolo[3,4-c] pyridin-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)- 1H-pyrazol-4-yl)picolinamide 389

5-Amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(4- cyanophenyl)thiazole-4- carboxamide 390

5-Amino-N-(5-(4- (aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5- fluoro-2-methoxyphenyl)thiazole-4-carboxamide 391

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-cyclopropyl-2- fluorophenyl)thiazole-4- carboxamide 392

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-cyclopropyl-1H-pyrazol-4-yl)-2-cyclopentenylthiazole-4- carboxamide 393

5-amino-2-(2,6-difluorophenyl)-N- (1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 394

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-ethyl-1H-pyrazol-4-yl)-2-cyclopentenylthiazole-4- carboxamide 395

5-amino-N-(5-(4-amino-3- fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide 396

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-ethyl-2-fluorophenyl)thiazole-4- carboxamide 397

5-amino-2-(2,6-difluorophenyl)-N- (1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 398

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-cyclopropyl-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4- carboxamide 399

5-amino-N-(5-(4-aminobut-1-ynyl)- 1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 400

5-amino-2-(2,6-difluorophenyl)-N- (1-(2-methoxyethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 401

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-ethyl-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4- carboxamide 402

5-amino-N-(5-((4S,5S)-4-amino-5- fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide 403

5-amino-N-(5-((4S,5R)-4-amino-5- fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide 404

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-3- isopropylphenyl)thiazole-4- carboxamide 405

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-cyclopropyl-1H-pyrazol-4-yl)-2-(2-fluoro-5- methylphenyl)thiazole-4- carboxamide 406

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-ethyl-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4- carboxamide 407

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-2-(2-fluoro-5- methylphenyl)thiazole-4- carboxamide 408

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-cyclopropyl-2- fluorophenyl)thiazole-4- carboxamide 409

5-amino-2-(2,6-difluorophenyl)-N- (1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 410

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-ethyl-2-fluorophenyl)thiazole-4- carboxamide 411

5-amino-2-(2,6-difluorophenyl)-N- (1-(2-(trifluoromethoxy)ethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 412

5-amino-2-(2,6-difluorophenyl)-N- (1-methyl-5-(5-(trifluoromethyl)-1,4-diazepan-1-yl)-1H-pyrazol-4- yl)thiazole-4-carboxamide 413

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-2-(2,5- difluorophenyl)thiazole-4- carboxamide 414

5-amino-N-(5-(6,6-difluoro-1,4- diazepan-1-yl)-1-methyl-1Hpyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide 415

5-amino-2-(2-fluorophenyl)-N-(5- (4-hydroxy-4-methylazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4- carboxamide 416

N-(5-(1,4-diazepan-1-yl)-1-(2,2- difluoroethyl)-1H-pyrazol-4-yl)-5-amino-2-(2,6- difluorophenyl)thiazole-4- carboxamide 417

5-amino-2-(2,6-difluorophenyl)-N- (1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide 418

5-amino-N-(5-(5-amino-4,4- difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide 419

5-amino-N-(5-(5-amino-4,4- difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide 420

(R)-5-amino-N-(5-(4-aminoazepan- 1-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-2-(2-fluoro-5- methylphenyl)thiazole-4- carboxamide 421

N-(5-(1,4-diazepan-1-yl)-1-(2,2- difluoroethyl)-1H-pyrazol-4-yl)-5-amino-2-(2-fluoro-5- methylphenyl)thiazole-4- carboxamide 422

N-(5-(1,4-diazepan-1-yl)-1-(2,2- difluoroethyl)-1H-pyrazol-4-yl)-5-amino-2-(2,5- difluorophenyl)thiazole-4- carboxamide 423

5-amino-N-(5-(3-aminoazepan-1- yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-2-(2,6- difluorophenyl)thiazole-4- carboxamide 424

5-amino-N-(1-cyclobutyl-1H- pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4- carboxamide 425

5-amino-2-(2,6-difluorophenyl)-N- (1-methyl-5-(6-methyl-1,4-diazepan-1-yl)-1H-pyrazol-4- yl)thiazole-4-carboxamide

The compounds of the present invention were tested for their capacity toinhibit Pim kinase activity and for their biological effects on growingcells as described below in Examples 901 and 902. Formula I compoundshaving Ki/IC_(50/)EC₅₀ of less than 1 μM in assays described in Examples901 and 902, may be useful therapeutically as Pim kinase inhibitors(Pim-1, Pim-2 and/or Pim-3).

The present invention includes a composition (e.g., a pharmaceuticalcomposition) comprising a compound of Formula I, and/or solvates,hydrates and/or salts thereof, and a carrier (a pharmaceuticallyacceptable carrier). The present invention also includes a composition(e.g., a pharmaceutical composition) comprising a compound of Formula Iand/or solvates, hydrates and/or salts thereof, and a carrier (apharmaceutically acceptable carrier), further comprising a secondchemotherapeutic agent such as those described herein. The presentcompositions are useful for inhibiting abnormal cell growth or treatinga hyperproliferative disorder such as cancer in a mammal (e.g., human).For example, the present compounds and compositions are useful fortreating multiple myeloma, lymphoma, acute myeloid leukemia, prostatecancer, breast cancer, hepatocellular carcinoma, pancreatic cancer,and/or colorectal cancer in a mammal (e.g., human).

The present invention includes a method of inhibiting abnormal cellgrowth or treating a hyperproliferative disorder such as cancer in amammal (e.g., human) comprising administering to said mammal atherapeutically effective amount of a compound of Formula I, and/orsolvates, hydrates and/or salts thereof, or a composition thereof. Forexample, the present invention includes a method of treating multiplemyeloma, lymphoma, acute myeloid leukemia, prostate cancer, breastcancer, hepatocellular carcinoma, pancreatic cancer, and/or colorectalcancer in a mammal (e.g., human), comprising administering to saidmammal a therapeutically effective amount of a compound of Formula I,and/or solvates, hydrates and/or salts thereof) or a compositionthereof.

The present invention includes a method of inhibiting abnormal cellgrowth or treating a hyperproliferative disorder such as cancer in amammal (e.g., human) comprising administering to said mammal atherapeutically effective amount of a compound of Formula I, and/orsolvates, hydrates and/or salts thereof, or a composition thereof, incombination with a second chemotherapeutic agent such as those describedherein. For example, the present invention includes a method of treatingmultiple myeloma, lymphoma, acute myeloid leukemia, prostate cancer,breast cancer, hepatocellular carcinoma, pancreatic cancer, and/orcolorectal cancer in a mammal (e.g., human), comprising administering tosaid mammal a therapeutically effective amount of a compound of FormulaI, and/or solvates, hydrates and/or salts thereof, or a compositionthereof, in combination with a second chemotherapeutic agent such asthose described herein.

The present invention includes a method of treating lymphoma in a mammal(e.g., human) comprising administering to said mammal a therapeuticallyeffective amount of a compound of Formula I, and/or solvates, hydratesand/or salts thereof, or a composition thereof, either alone or incombination with a second chemotherapeutic agent such as an anti-B-cellantibody therapeutic (e.g., Rituxan and/or Dacetuzumab), gemcitabine,corticosteroids (e.g., prednisolone and/or dexamethasone), chemotherapycocktails (e.g., CHOP (cyclophosphamide, doxorubicin, vincristine,prednisolone) and/or ICE (isfosfamide, cytoxan, etoposide)), acombination of biologics and chemotherapy (e.g., Rituxan-ICE,Dacetuzumab-Rituxan-ICE, R-Gem, and/or D-R-Gem), an Akt inhibitor, aPI3K inhibitor (e.g, GDC-0941 (Genentech) and/or GDC-0980 (Genentech)),rapamycin, a MEK inhibitor (GDC-0973), a Bcl-2 inhibitor (ABT-263), andlymphoma directed antibody drug conjugate (e.g., antiCD22 antibody drugconjugate including but not limited to antiCD22-vcMMAE, and/orantiCD79b-antibody drug conjugate including but not limited toantiCD79b-vcMMAE).

The present invention includes a method of treating multiple myeloma ina mammal (e.g., human) comprising administering to said mammal atherapeutically effective amount of a compound of Formula I, and/orsolvates, hydrates and/or salts thereof, or a composition thereof,either alone or in combination with a second chemotherapeutic agent suchas melphalan, “Imids” (e.g., thalidomide, lenalidomide, and/orpomolidamide), corticosteroids (e.g., dexamethasone and/orprednisolone), and bortezomib or other proteasome inhibitor.

The present invention includes a method of treating multiple myeloma,chronic lymphocytic leukemia (CLL), or acute myeloid leukemia (AML) in amammal (e.g., human) comprising administering to said mammal atherapeutically effective amount of a compound of Formula I, and/orsolvates, hydrates and/or salts thereof, or a composition thereof,either alone or in combination with a second chemotherapeutic agent suchas cytarabine (araC), anthracyclines (e.g., daunorubicin and/oridarubicin), anti-myeloid antibody therapeutics (e.g., SGN-33),anti-myeloid antibody-drug conjugates (e.g., MYLOTARG®).

The present invention includes a method of treating chronic lymphocyticleukemia (CLL) in a mammal (e.g., human) comprising administering tosaid mammal a therapeutically effective amount of a compound of FormulaI, and/or solvates, hydrates and/or salts thereof, or a compositionthereof, either alone or in combination with a second chemotherapeuticagent such as fludarabine, cyclophosphamide, anti-B-cell antibodytherapeutics (e.g., Rituxan and/or Dacetuzumab).

The present invention includes a method of treating chronic myeloidleukemia (CML) in a mammal (e.g., human) comprising administering tosaid mammal a therapeutically effective amount of a compound of FormulaI, and/or solvates, hydrates and/or salts thereof, or a compositionthereof, either alone or in combination with a second chemotherapeuticagent such as a BCR-abl inhibitor (e.g., imatinib, nilotinib, and/ordasatinib).

The present invention includes a method of treating myelodysplasticdiseases (MDS) and myeloproliferative disorders including polycythemiavera (PV), essential thrombocytosis (ET) or myelofibrosis (MF), in amammal (e.g., human) comprising administering to said mammal atherapeutically effective amount of a compound of Formula I, and/orsolvates, hydrates and/or salts thereof, or a composition thereof,either alone or in combination.

The present invention includes a method of using the present compoundsfor in vitro, in situ, and in vivo diagnosis or treatment of mammaliancells, organisms, or associated pathological conditions.

Administration of the compounds of the present invention (hereinafterthe “active compound(s)”) can be effected by any method that enablesdelivery of the compounds to the site of action. These methods includeoral routes, intraduodenal routes, parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion),topical, inhalation and rectal administration.

The amount of the active compound administered will be dependent on thesubject being treated, the severity of the disorder or condition, therate of administration, the disposition of the compound and thediscretion of the prescribing physician. However, an effective dosage isin the range of about 0.001 to about 100 mg per kg body weight per day,preferably about 1 to about 35 mg/kg/day, in single or divided doses.For a 70 kg human, this would amount to about 0.05 to 7 g/day,preferably about 0.05 to about 2.5 g/day. In some instances, dosagelevels below the lower limit of the aforesaid range may be more thanadequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, provided that such larger dosesare first divided into several small doses for administration throughoutthe day.

The active compound may be applied as a sole therapy or in combinationwith one or more chemotherapeutic agents, for example those describedherein. Such conjoint treatment may be achieved by way of thesimultaneous, sequential or separate dosing of the individual componentsof treatment.

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, pill, powder, sustainedrelease formulations, solution, suspension for parenteral injection as asterile solution, suspension or emulsion for topical administration asan ointment or cream or for rectal administration as a suppository. Thepharmaceutical composition may be in unit dosage forms suitable forsingle administration of precise dosages. The pharmaceutical compositionwill include a conventional pharmaceutical carrier or excipient and acompound according to the invention as an active ingredient. Inaddition, it may include other medicinal or pharmaceutical agents,carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of Formula I compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers,water and various organic solvents. The pharmaceutical compositions may,if desired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch, alginic acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tablettingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Preferred materials, therefore,include lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration the active compound therein may be combined with varioussweetening or flavoring agents, coloring matters or dyes and, ifdesired, emulsifying agents or suspending agents, together with diluentssuch as water, ethanol, propylene glycol, glycerin, or combinationsthereof.

Methods of preparing various pharmaceutical compositions with a specificamount of active compound are known, or will be apparent, to thoseskilled in this art. For examples, see Remington's PharmaceuticalSciences, Mack Publishing Company, Ester, Pa., 15.sup.th Edition (1975).

Administration of Formula I Compounds

The Formula I compounds of the invention may be administered by anyroute appropriate to the condition to be treated. Suitable routesinclude oral, parenteral (including subcutaneous, intramuscular,intravenous, intraarterial, intradermal, intrathecal and epidural),transdermal, rectal, nasal, topical (including buccal and sublingual),vaginal, intraperitoneal, intrapulmonary and intranasal. For localimmunosuppressive treatment, the compounds may be administered byintralesional administration, including perfusing or otherwisecontacting the graft with the inhibitor before transplantation. It willbe appreciated that the preferred route may vary with for example thecondition of the recipient. Where the compound is administered orally,it may be formulated as a pill, capsule, tablet, etc. with apharmaceutically acceptable carrier or excipient. Where the compound isadministered parenterally, it may be formulated with a pharmaceuticallyacceptable parenteral vehicle and in a unit dosage injectable form, asdetailed below.

A dose to treat human patients may range from about 10 mg to about 1000mg of Formula I compound. A typical dose may be about 100 mg to about300 mg of the compound. A dose may be administered once a day (QID),twice per day (BID), or more frequently, depending on thepharmacokinetic and pharmacodynamic properties, including absorption,distribution, metabolism, and excretion of the particular compound. Inaddition, toxicity factors may influence the dosage and administrationregimen. When administered orally, the pill, capsule, or tablet may beingested daily or less frequently for a specified period of time. Theregimen may be repeated for a number of cycles of therapy.

Methods of Treatment with Formula I Compounds

Compounds of the present invention are useful for treatinghyperproliferative diseases, conditions and/or disorders including, butnot limited to, those characterized by over expression of Pim kinases,e.g. Pim-1, Pim-2 and Pim-3 kinases. Accordingly, another aspect of thisinvention includes methods of treating or preventing diseases orconditions that can be treated or prevented by inhibiting Pim kinase. Inone embodiment, the method comprises administering to a mammal in needthereof a therapeutically effective amount of a compound of Formula I,or a stereoisomer, geometric isomer, tautomer, or pharmaceuticallyacceptable salt thereof. In one embodiment, a human patient is treatedwith a compound of Formula I and a pharmaceutically acceptable carrier,adjuvant, or vehicle, wherein said compound of Formula I is present inan amount to detectably inhibit Pim kinase activity.

Cancers which can be treated according to the methods of this inventioninclude, but are not limited to, breast, ovary, cervix, prostate,testis, genitourinary tract, esophagus, larynx, glioblastoma,neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoidcarcinoma, large cell carcinoma, non-small cell lung carcinoma (NSCLC),small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma,pancreas, adenocarcinoma, thyroid, follicular carcinoma,undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma,sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidneycarcinoma, myeloid disorders, lymphoid disorders, hairy cells, buccalcavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine,colon-rectum, large intestine, rectum, brain and central nervous system,Hodgkin's and leukemia.

Another aspect of this invention provides a compound of this inventionfor use in the treatment of the diseases or conditions described hereinin a mammal, for example, a human, suffering from such disease orcondition. Also provided is the use of a compound of this invention inthe preparation of a medicament for the treatment of the diseases andconditions described herein in a warm-blooded animal, such as a mammal,for example a human, suffering from such disorder.

Pharmaceutical Formulations

In order to use a Formula I compound for the therapeutic treatment(including prophylactic treatment) of mammals including humans, it isnormally formulated in accordance with standard pharmaceutical practiceas a pharmaceutical composition. According to this aspect of theinvention there is provided a pharmaceutical composition comprising acompound of this invention in association with a pharmaceuticallyacceptable diluent or carrier.

A typical formulation is prepared by mixing a Formula I compound and acarrier, diluent or excipient. Suitable carriers, diluents andexcipients are well known to those skilled in the art and includematerials such as carbohydrates, waxes, water soluble and/or swellablepolymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents,water and the like. The particular carrier, diluent or excipient usedwill depend upon the means and purpose for which the compound of thepresent invention is being applied. Solvents are generally selectedbased on solvents recognized by persons skilled in the art as safe(GRAS) to be administered to a mammal. In general, safe solvents arenon-toxic aqueous solvents such as water and other non-toxic solventsthat are soluble or miscible in water. Suitable aqueous solvents includewater, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400,PEG 300), etc. and mixtures thereof. The formulations may also includeone or more buffers, stabilizing agents, surfactants, wetting agents,lubricating agents, emulsifiers, suspending agents, preservatives,antioxidants, opaquing agents, glidants, processing aids, colorants,sweeteners, perfuming agents, flavoring agents and other known additivesto provide an elegant presentation of the drug (i.e., a compound of thepresent invention or pharmaceutical composition thereof) or aid in themanufacturing of the pharmaceutical product (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., compoundof the present invention or stabilized form of the Formula I compound(e.g., complex with a cyclodextrin derivative or other knowncomplexation agent) is dissolved in a suitable solvent in the presenceof one or more of the excipients described above. The compound of thepresent invention is typically formulated into pharmaceutical dosageforms to provide an easily controllable dosage of the drug and to enablepatient compliance with the prescribed regimen.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. Generally, an article for distribution includesa container having deposited therein the pharmaceutical formulation inan appropriate form. Suitable containers are well known to those skilledin the art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

Pharmaceutical formulations of the compounds of the present inventionmay be prepared for various routes and types of administration. Forexample, a compound of Formula I having the desired degree of purity mayoptionally be mixed with pharmaceutically acceptable diluents, carriers,excipients or stabilizers (Remington's Pharmaceutical Sciences (1980)16^(th) edition, Osol, A. Ed.), in the form of a lyophilizedformulation, milled powder, or an aqueous solution. Formulation may beconducted by mixing at ambient temperature at the appropriate pH, and atthe desired degree of purity, with physiologically acceptable carriers,i.e., carriers that are non-toxic to recipients at the dosages andconcentrations employed. The pH of the formulation depends mainly on theparticular use and the concentration of compound, but may range fromabout 3 to about 8. Formulation in an acetate buffer at pH 5 is asuitable embodiment.

The compound of this invention for use herein is preferably sterile. Inparticular, formulations to be used for in vivo administration must besterile. Such sterilization is readily accomplished by filtrationthrough sterile filtration membranes.

The compound ordinarily can be stored as a solid composition, alyophilized formulation or as an aqueous solution.

The pharmaceutical compositions of the invention comprising a Formula Icompound will be formulated, dosed and administered in a fashion, i.e.,amounts, concentrations, schedules, course, vehicles and route ofadministration, consistent with good medical practice. Factors forconsideration in this context include the particular disorder beingtreated, the particular mammal being treated, the clinical condition ofthe individual patient, the cause of the disorder, the site of deliveryof the agent, the method of administration, the scheduling ofadministration, and other factors known to medical practitioners. The“therapeutically effective amount” of the compound to be administeredwill be governed by such considerations, and is the minimum amountnecessary to prevent, ameliorate, or treat the coagulation factormediated disorder. Such amount is preferably below the amount that istoxic to the host or renders the host significantly more susceptible tobleeding.

As a general proposition, the initial pharmaceutically effective amountof the Formula I compound administered parenterally per dose will be inthe range of about 0.01-100 mg/kg, namely about 0.1 to 20 mg/kg ofpatient body weight per day, with the typical initial range of compoundused being 0.3 to 15 mg/kg/day.

Acceptable diluents, carriers, excipients and stabilizers are nontoxicto recipients at the dosages and concentrations employed, and includebuffers such as phosphate, citrate and other organic acids; antioxidantsincluding ascorbic acid and methionine; preservatives (such asoctadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride, benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionicsurfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Theactive pharmaceutical ingredients may also be entrapped in microcapsulesprepared, for example, by coacervation techniques or by interfacialpolymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington's Pharmaceutical Sciences 16^(th) edition, Osol, A. Ed.(1980).

Sustained-release preparations of Formula I compounds may be prepared.Suitable examples of sustained-release preparations includesemipermeable matrices of solid hydrophobic polymers containing acompound of Formula I, which matrices are in the form of shapedarticles, e.g., films, or microcapsules. Examples of sustained-releasematrices include polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides(U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid andgamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate,degradable lactic acid-glycolic acid copolymers such as the LUPRONDEPOT™ (injectable microspheres composed of lactic acid-glycolic acidcopolymer and leuprolide acetate) and poly-D-(−)-3-hydroxybutyric acid.

The formulations include those suitable for the administration routesdetailed herein. The formulations may conveniently be presented in unitdosage form and may be prepared by any of the methods well known in theart of pharmacy. Techniques and formulations generally are found inRemington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.).Such methods include the step of bringing into association the activeingredient with the carrier which constitutes one or more accessoryingredients. In general the formulations are prepared by uniformly andintimately bringing into association the active ingredient with liquidcarriers or finely divided solid carriers or both, and then, ifnecessary, shaping the product.

Formulations of a compound of Formula I suitable for oral administrationmay be prepared as discrete units such as pills, capsules, cachets ortablets each containing a predetermined amount of a compound of FormulaI.

Compressed tablets may be prepared by compressing in a suitable machinethe active ingredient in a free-flowing form such as a powder orgranules, optionally mixed with a binder, lubricant, inert diluent,preservative, surface active or dispersing agent. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent. The tablets mayoptionally be coated or scored and optionally are formulated so as toprovide slow or controlled release of the active ingredient therefrom.

Tablets, troches, lozenges, aqueous or oil suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, e.g., gelatincapsules, syrups or elixirs may be prepared for oral use. Formulationsof compounds of Formula I intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents including sweetening agents, flavoring agents, coloringagents and preserving agents, in order to provide a palatablepreparation. Tablets containing the active ingredient in admixture withnon-toxic pharmaceutically acceptable excipient which are suitable formanufacture of tablets are acceptable. These excipients may be, forexample, inert diluents, such as calcium or sodium carbonate, lactose,calcium or sodium phosphate; granulating and disintegrating agents, suchas maize starch, or alginic acid; binding agents, such as starch,gelatin or acacia; and lubricating agents, such as magnesium stearate,stearic acid or talc. Tablets may be uncoated or may be coated by knowntechniques including microencapsulation to delay disintegration andadsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate alone or with a wax may beemployed.

For treatment of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w. When formulated in an ointment, the active ingredientsmay be employed with either a paraffinic or a water-miscible ointmentbase. Alternatively, the active ingredients may be formulated in a creamwith an oil-in-water cream base.

If desired, the aqueous phase of the cream base may include a polyhydricalcohol, i.e., an alcohol having two or more hydroxyl groups such aspropylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol andpolyethylene glycol (including PEG 400) and mixtures thereof. Thetopical formulations may desirably include a compound which enhancesabsorption or penetration of the active ingredient through the skin orother affected areas. Examples of such dermal penetration enhancersinclude dimethyl sulfoxide and related analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it desirably comprises a mixture of at least oneemulsifier with a fat or oil, or with both a fat and an oil. Preferably,a hydrophilic emulsifier is included together with a lipophilicemulsifier which acts as a stabilizer. It is also preferred to includeboth an oil and a fat. Together, the emulsifier(s) with or withoutstabilizer(s) make up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

Aqueous suspensions of Formula I compounds contain the active materialsin admixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, croscarmellose, povidone, methylcellulose,hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone,gum tragacanth and gum acacia, and dispersing or wetting agents such asa naturally occurring phosphatide (e.g., lecithin), a condensationproduct of an alkylene oxide with a fatty acid (e.g., polyoxyethylenestearate), a condensation product of ethylene oxide with a long chainaliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensationproduct of ethylene oxide with a partial ester derived from a fatty acidand a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Theaqueous suspension may also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such as sucroseor saccharin.

The pharmaceutical compositions of compounds of Formula I may be in theform of a sterile injectable preparation, such as a sterile injectableaqueous or oleaginous suspension. This suspension may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents which have been mentioned above. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butanediol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of about 0.5 to 20% w/w, for exampleabout 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration may beprepared according to conventional methods and may be delivered withother therapeutic agents such as compounds heretofore used in thetreatment or prophylaxis disorders as described below.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

The formulations may be packaged in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water, for injection immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier therefore. Veterinary carriers are materials useful for thepurpose of administering the composition and may be solid, liquid orgaseous materials which are otherwise inert or acceptable in theveterinary art and are compatible with the active ingredient. Theseveterinary compositions may be administered parenterally, orally or byany other desired route.

Combination Therapy

The compounds of Formula I may be employed alone or in combination withother therapeutic agents for the treatment of a disease or disorderdescribed herein, such as a hyperproliferative disorder (e.g., cancer).In certain embodiments, a compound of Formula I is combined in apharmaceutical combination formulation, or dosing regimen as combinationtherapy, with a second compound that has anti-hyperproliferativeproperties or that is useful for treating a hyperproliferative disorder(e.g., cancer). The second compound of the pharmaceutical combinationformulation or dosing regimen preferably has complementary activities tothe compound of Formula I such that they do not adversely affect eachother. Such compounds are suitably present in combination in amountsthat are effective for the purpose intended. In one embodiment, acomposition of this invention comprises a compound of Formula I, incombination with a chemotherapeutic agent such as described herein.

The combination therapy may be administered as a simultaneous orsequential regimen. When administered sequentially, the combination maybe administered in two or more administrations. The combinedadministration includes coadministration, using separate formulations ora single pharmaceutical formulation, and consecutive administration ineither order, wherein preferably there is a time period while both (orall) active agents simultaneously exert their biological activities.

Suitable dosages for any of the above coadministered agents are thosepresently used and may be lowered due to the combined action (synergy)of the newly identified agent and other chemotherapeutic agents ortreatments.

The combination therapy may provide “synergy” and prove “synergistic”,i.e., the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect may be attained when theactive ingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined, unit dosage formulation; (2) delivered byalternation or in parallel as separate formulations; or (3) by someother regimen. When delivered in alternation therapy, a synergisticeffect may be attained when the compounds are administered or deliveredsequentially, e.g., by different injections in separate syringes,separate pills or capsules, or separate infusions. In general, duringalternation therapy, an effective dosage of each active ingredient isadministered sequentially, i.e., serially, whereas in combinationtherapy, effective dosages of two or more active ingredients areadministered together.

In a particular embodiment of anti-cancer therapy, a compound of FormulaI, or a stereoisomer, geometric isomer, tautomer, solvate, metabolite,or pharmaceutically acceptable salt or prodrug thereof, may be combinedwith other chemotherapeutic, hormonal or antibody agents such as thosedescribed herein, as well as combined with surgical therapy andradiotherapy. Combination therapies according to the present inventionthus comprise the administration of at least one compound of Formula I,or a stereoisomer, geometric isomer, tautomer, solvate, metabolite, orpharmaceutically acceptable salt or prodrug thereof, and the use of atleast one other cancer treatment method. The amounts of the compound(s)of Formula I and the other pharmaceutically active chemotherapeuticagent(s) and the relative timings of administration will be selected inorder to achieve the desired combined therapeutic effect.

Metabolites of Formula I Compounds

Also falling within the scope of this invention are the in vivometabolic products of Formula I described herein. Such products mayresult for example from the oxidation, reduction, hydrolysis, amidation,deamidation, esterification, deesterification, enzymatic cleavage, andthe like, of the administered compound. Accordingly, the inventionincludes metabolites of compounds of Formula I, including compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof.

Metabolite products typically are identified by preparing aradiolabelled (e.g., ¹⁴C or ³H) isotope of a compound of the invention,administering it parenterally in a detectable dose (e.g., greater thanabout 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, orto man, allowing sufficient time for metabolism to occur (typicallyabout 30 seconds to 30 hours) and isolating its conversion products fromthe urine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well known tothose skilled in the art. The metabolite products, so long as they arenot otherwise found in vivo, may be useful in diagnostic assays fortherapeutic dosing of the compounds of the invention.

Articles of Manufacture

In another embodiment of the invention, an article of manufacture, or“kit”, containing materials useful for the treatment of the diseases anddisorders described above is provided. The kit comprises a containercomprising a compound of Formula I. The kit may further comprise a labelor package insert, on or associated with the container. The term“package insert” is used to refer to instructions customarily includedin commercial packages of therapeutic products, that contain informationabout the indications, usage, dosage, administration, contraindicationsand/or warnings concerning the use of such therapeutic products.Suitable containers include, for example, bottles, vials, syringes,blister pack, etc. The container may be formed from a variety ofmaterials such as glass or plastic. The container may hold a compound ofFormula I or II or a formulation thereof which is effective for treatingthe condition and may have a sterile access port (for example, thecontainer may be an intravenous solution bag or a vial having a stopperpierceable by a hypodermic injection needle). At least one active agentin the composition is a compound of Formula I. The label or packageinsert indicates that the composition is used for treating the conditionof choice, such as cancer. In addition, the label or package insert mayindicate that the patient to be treated is one having a disorder such asa hyperproliferative disorder, neurodegeneration, cardiac hypertrophy,pain, migraine or a neurotraumatic disease or event. In one embodiment,the label or package inserts indicates that the composition comprising acompound of Formula I can be used to treat a disorder resulting fromabnormal cell growth. The label or package insert may also indicate thatthe composition can be used to treat other disorders. Alternatively, oradditionally, the article of manufacture may further comprise a secondcontainer comprising a pharmaceutically acceptable buffer, such asbacteriostatic water for injection (BWFI), phosphate-buffered saline,Ringer's solution and dextrose solution. It may further include othermaterials desirable from a commercial and user standpoint, includingother buffers, diluents, filters, needles, and syringes.

The kit may further comprise directions for the administration of thecompound of Formula I and, if present, the second pharmaceuticalformulation. For example, if the kit comprises a first compositioncomprising a compound of Formula I, and a second pharmaceuticalformulation, the kit may further comprise directions for thesimultaneous, sequential or separate administration of the first andsecond pharmaceutical compositions to a patient in need thereof.

In another embodiment, the kits are suitable for the delivery of solidoral forms of a compound of Formula I, such as tablets or capsules. Sucha kit preferably includes a number of unit dosages. Such kits caninclude a card having the dosages oriented in the order of theirintended use. An example of such a kit is a “blister pack”. Blisterpacks are well known in the packaging industry and are widely used forpackaging pharmaceutical unit dosage forms. If desired, a memory aid canbe provided, for example in the form of numbers, letters, or othermarkings or with a calendar insert, designating the days in thetreatment schedule in which the dosages can be administered.

According to one embodiment, a kit may comprise (a) a first containerwith a compound of Formula I contained therein; and optionally (b) asecond container with a second pharmaceutical formulation containedtherein, wherein the second pharmaceutical formulation comprises asecond compound with anti-hyperproliferative activity. Alternatively, oradditionally, the kit may further comprise a third container comprisinga pharmaceutically-acceptable buffer, such as bacteriostatic water forinjection (BWFI), phosphate-buffered saline, Ringer's solution anddextrose solution. It may further include other materials desirable froma commercial and user standpoint, including other buffers, diluents,filters, needles, and syringes.

In certain other embodiments wherein the kit comprises a composition ofFormula I and a second therapeutic agent, the kit may comprise acontainer for containing the separate compositions such as a dividedbottle or a divided foil packet, however, the separate compositions mayalso be contained within a single, undivided container. Typically, thekit comprises directions for the administration of the separatecomponents. The kit form is particularly advantageous when the separatecomponents are preferably administered in different dosage forms (e.g.,oral and parenteral), are administered at different dosage intervals, orwhen titration of the individual components of the combination isdesired by the prescribing physician.

Preparation of Formula I Compounds

Compounds of Formula I may be synthesized by synthetic routes thatinclude processes analogous to those well-known in the chemical arts,particularly in light of the description contained herein, and those forother heterocycles described in: Comprehensive Heterocyclic ChemistryII, Editors Katritzky and Rees, Elsevier, 1997, e.g. Volume 3; LiebigsAnnalen der Chemie, (9):1910-16, (1985); Helvetica Chimica Acta,41:1052-60, (1958); Arzneimittel-Forschung, 40(12):1328-31, (1990), eachof which are expressly incorporated by reference. Starting materials aregenerally available from commercial sources such as Aldrich Chemicals(Milwaukee, Wis.) or are readily prepared using methods well known tothose skilled in the art (e.g., prepared by methods generally describedin Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-23, Wiley, N.Y. (1967-2006 ed.), or Beilsteins Handbuch derorganischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, includingsupplements (also available via the Beilstein online database).

Synthetic chemistry transformations and protecting group methodologies(protection and deprotection) useful in synthesizing Formula I compoundsand necessary reagents and intermediates are known in the art andinclude, for example, those described in R. Larock, ComprehensiveOrganic Transformations, VCH Publishers (1989); T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., John Wileyand Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents forOrganic Synthesis, John Wiley and Sons (1995) and subsequent editionsthereof.

Compounds of Formula I may be prepared singly or as compound librariescomprising at least 2, for example 5 to 1,000 compounds, or 10 to 100compounds. Libraries of compounds of Formula I may be prepared by acombinatorial ‘split and mix’ approach or by multiple parallel synthesesusing either solution phase or solid phase chemistry, by proceduresknown to those skilled in the art. Thus according to a further aspect ofthe invention there is provided a compound library comprising at least 2compounds, or pharmaceutically acceptable salts thereof.

The General Procedures and Examples provide exemplary methods forpreparing Formula I compounds. Those skilled in the art will appreciatethat other synthetic routes may be used to synthesize the Formula Icompounds. Although specific starting materials and reagents aredepicted and discussed in the Figures, General Procedures, and Examples,other starting materials and reagents can be easily substituted toprovide a variety of derivatives and/or reaction conditions. Inaddition, many of the exemplary compounds prepared by the describedmethods can be further modified in light of this disclosure usingconventional chemistry well known to those skilled in the art.

In preparing compounds of Formulas I, protection of remote functionality(e.g., primary or secondary amine) of intermediates may be necessary.The need for such protection will vary depending on the nature of theremote functionality and the conditions of the preparation methods.Suitable amino-protecting groups include acetyl, trifluoroacetyl,t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection isreadily determined by one skilled in the art. For a general descriptionof protecting groups and their use, see T. W. Greene, Protective Groupsin Organic Synthesis, John Wiley & Sons, New York, 1991.

Methods of Separation

In the methods of preparing Formula I compounds, it may be advantageousto separate reaction products from one another and/or from startingmaterials. The desired products of each step or series of steps isseparated and/or purified to the desired degree of homogeneity by thetechniques common in the art. Typically such separations involvemultiphase extraction, crystallization from a solvent or solventmixture, distillation, sublimation, or chromatography. Chromatographycan involve any number of methods including, for example: reverse-phaseand normal phase; size exclusion; ion exchange; high, medium and lowpressure liquid chromatography methods and apparatus; small scaleanalytical; simulated moving bed (SMB) and preparative thin or thicklayer chromatography, as well as techniques of small scale thin layerand flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like. Selection of appropriate methodsof separation depends on the nature of the materials involved, such as,boiling point and molecular weight in distillation and sublimation,presence or absence of polar functional groups in chromatography,stability of materials in acidic and basic media in multiphaseextraction, and the like.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers. Also,some of the compounds of the present invention may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of a chiral HPLCcolumn.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S. “Stereochemistry of OrganicCompounds,” John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H.,(1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: “DrugStereochemistry, Analytical Methods and Pharmacology,” Irving W. Wainer,Ed., Marcel Dekker, Inc., New York (1993).

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(E. and Wilen, S. “Stereochemistry of Organic Compounds”, John Wiley &Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed byreacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral esters, such as a menthyl ester, e.g., (−) menthylchloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem.(1982) 47:4165), of the racemic mixture, and analyzing the ¹H NMRspectrum for the presence of the two atropisomeric enantiomers ordiastereomers. Stable diastereomers of atropisomeric compounds can beseparated and isolated by normal- and reverse-phase chromatographyfollowing methods for separation of atropisomeric naphthyl-isoquinolines(WO 96/15111). By method (3), a racemic mixture of two enantiomers canbe separated by chromatography using a chiral stationary phase (“ChiralLiquid Chromatography” (1989) W. J. Lough, Ed., Chapman and Hall, NewYork; Okamoto, J. Chromatogr., (1990) 513:375-378). Enriched or purifiedenantiomers can be distinguished by methods used to distinguish otherchiral molecules with asymmetric carbon atoms, such as optical rotationand circular dichroism.

General Preparative Procedures

FIG. 1 shows an exemplary synthesis of 4-aminopyrazole compounds 5.4-nitro-1H-pyrazole 1 is converted to 2 by treatment with a base in asuitable solvent or neat, followed by the addition of an alkylationreagent such as dimethyl sulfate. Compound 2 may be converted tocompound 3 by treatment with a base such as lithiumhexamethyldisilazide, or nBuLi in a suitable solvent at an appropriatetemperature, such as THF at −78° C. Compound 3 may be converted tocompound 4 by direct SnAr or Suzuki conditions described in theliterature. Compound 5 may be synthesized from 4 by a suitable reductionmethod, such as by ion in the presence of a weak Lewis acid such asammonium chloride in a suitable solvent such as ethanol or water, or bytreatment with zinc powder and ammonium formate in tetrahydrofuran, orhydrogenation with H₂ and transitional metal catalysts such as palladiumon carbon.

FIG. 2 shows an exemplary synthesis of 4-carboxy-thiazoles 11 fromhydroxamide compounds 6. Reduction of 6 by a reducing reagent in asuitable solvent such as Na₂S₂O₃ in water gives 7, which may beconverted to 8 by an acylating reagent in a suitable solvent with asuitable base such as benzoyl chloride in dichloromethane with sodiumbicarbonate. Compound 8 may be converted to 9 by a sulfur containingreagent in a suitable reagent such as Lawesson's reagent in pyridine,and protected to 10 by a suitable Boc-protecting group. Ester hydrolysisof 10 using a suitable base and solvent, such as LiOH in methanol andwater gives 11.

FIG. 3 shows an exemplary synthesis of 2-substituted,4-carboxy-5-aminothiazoles 11 by C-2 bromination of 12 followed bySuzuki reaction of 13.

The Suzuki-type coupling reaction is useful to attach a heterocycle or aheteroaryl by displacing a halide at the 2-position of the thiazole,pyridyl, or picolinyl ring in the synthesis of a Formula I compound. Forexample, 2-bromo (or chloro) thiazole 11 may be reacted with about 1.5equivalents of a aryl, heterocyclyl or heteroaryl boronic acid or esterreagent and an excess of aqueous sodium carbonate in acetonitrile. Acatalytic amount, or more, of a low valent palladium reagent, such asbis(triphenylphosphine)palladium(II) dichloride, is added. A variety ofboronic acids or boronic esters can be used. Boronic esters includedpinacole esters (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl). Also, anitrogen of a heterocycle or heteroaryl may be protected, for example asN-THP. In some cases potassium acetate is used in place of sodiumcarbonate to adjust the pH of the aqueous layer. The reaction may beheated to about 140-150° C. under pressure in a microwave reactor suchas the Biotage Optimizer (Biotage, Inc.) for 10 to 30 minutes. Thecontents are extracted with ethyl acetate, or another organic solvent.After evaporation of the organic layer the Suzuki coupling product maybe purified on silica or by reverse phase HPLC.

A variety of palladium catalysts can be used during the Suzuki couplingstep to form exemplary Formula I compounds. Low valent, Pd(II) and Pd(0)catalysts may be used in the Suzuki coupling reaction, includingPdCl2(PPh₃)₂, Pd(t-Bu)₃, PdCl₂ dppf CH₂Cl₂, Pd(PPh₃)₄, Pd(Oac)/PPh₃,Cl₂Pd[(Pet₃)]₂, Pd(DIPHOS)₂, Cl₂Pd(Bipy), [PdCl(Ph₂PCH₂PPh₂)]₂,Cl₂Pd[P(o-tol)₃]₂, Pd₂(dba)₃/P(o-tol)₃, Pd₂(dba)/P(furyl)₃,Cl₂Pd[P(furyl)₃]₂, Cl₂Pd(PmePh₂)₂, Cl₂Pd[P(4-F-Ph)₃]₂, Cl₂Pd[P(C₆F₆)₃]₂,Cl₂Pd[P(2-COOH-Ph)(Ph)₂]₂, Cl₂Pd[P(4-COOH-Ph)(Ph)₂]₂, and encapsulatedcatalysts Pd EnCat™ 30, Pd EnCat™ TPP30, and Pd(II)EnCat™ BINAP30 (US2004/0254066).

FIG. 4 shows an exemplary synthesis of5-amino-N-(pyrazol-4-yl)thiazole-carboxamide compounds 18 from couplingof 3,4-diaminopyrazole compounds 14 and 2-substituted,4-carboxy-5-aminothiazoles 11.

FIG. 5 shows an exemplary synthesis of6-amino-N-(pyrazol-4-yl)pyridyl-carboxamide compounds 22 from couplingof 3,4-diaminopyrazole compounds 14 and 6-substituted,2-carboxy-3-aminopyridyl compounds 19.

FIG. 6 shows an exemplary synthesis of6-amino-N-(pyrazol-4-yl)picolinic-carboxamide compounds 26 from couplingof 3,4-diaminopyrazole compounds 14 and 5-substituted,3-carboxy-2-aminopicolinyl compounds 23.

EXAMPLES Intermediates Example 1 5-chloro-1-methyl-4-nitro-1H-pyrazole

To a 500 mL round bottom flask containing 4-nitro-1-H-pyrazole (5 g,44.2 mmol) was added sodium hydroxide (1M, 200 mL) and dimethyl sulfate(31 mL, 330 mmol). The mixture was stirred at room temperature for 72 hand the mixture was extracted with CH₂Cl₂ (2×150 mL). The organic layerwas separated and the solvent was distilled off to yield1-methyl-4-nitro-1H-pyrazole as a white solid (4.30 g, 76%).

Following WO 2007/99326, to a 500 mL 3-neck-round bottom flask was added1-methyl-4-nitro-1H-pyrazole (4.30 g, 33.8 mmol) and THF (12 mL). Themixture was cooled to −78° C. and lithium hexamethyldisilazide in THF(1M, 88.4 mL, 90 mmol) was added dropwise via an addition funnel over 20min. The brown mixture was stirred for 30 min and warmed to −45 C over30 min. The mixture was cooled back down to −78° C. and hexachloroethane(10.5 g, 44.2 mmol) dissolved in THF (20 mL) was added via an additionfunnel over 15 min. The mixture was stirred for 2.5 h, warmed from −78 Cto −40 C and the reaction was monitored by LCMS. Upon completion of thereaction, the reaction was quenched with a solution of saturated NH₄Cl(150 mL), and ethyl acetate (100 mL) was added. The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate (100mL). The combined organic layer was washed with water (150 mL), driedover Na₂SO₄ and the organic solvent was distilled off. The crude productwas purified via flash chromatography (CH₂Cl₂/7% MeOH) to yield5-chloro-1-methyl-4-nitro-1H-pyrazole as a white solid (1.40 g, 20%). ¹HNMR (400 MHz, CDCl₃) δ 8.13 (s, 1H), 3.92 (s, 3H); ESIMS m/z=162.0 (M+1)

Example 2 tert-butyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate

To a 10 mL microwave vial was added5-chloro-1-methyl-4-nitro-1H-pyrazole (150 mg, 0.93 mmol), tert-butylazepan-4-ylcarbamate (220 mg, 1.02 mmol). Ethanol (4 mL) anddiisopropylethylamine (1.00 mL, 8.00 mmol) were added and the mixturewas irradiated with a microwave for 60 min at 130° C. The mixture wascooled, concentrated and purified via flash chromatography,heptane/ethyl acetate 20% to 80% to afford yellow oil (306 mg, 97%).

To a 50 mL round bottom flask was added the nitro compound (306 mg, 0.90mmol), iron (202 mg, 3.61 mmol), ammonium chloride (241 mg, 4.5 mmol),ethanol (10 mL) and water (1.5 mL). The mixture was stirred for 1 h at60° C. and the reaction was monitored by LCMS. Upon completion of thereaction, the mixture was filtered through a pad of Celite and waswashed with ethyl acetate (30 mL) and a 10% aqueous solution of K₃PO₄(30 mL). The organic layer was washed with water (30 mL), dried overNa₂SO₄ and the organic solvent was distilled off to yield tert-butyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate as a brown oilwith a purity of >98% (264 mg, 95%). ESIMS m/z=310.1 (M+1).

Example 3 tert-butyl1-(1-methyl-4-amino-1H-pyrazol-5-yl)piperidin-4-ylcarbamate

Following the procedures as described in Example 2 and starting withtert-butyl piperidin-4-ylcarbamate, tert-butyl1-(1-methyl-4-amino-1H-pyrazol-5-yl)piperidin-4-ylcarbamate was obtainedas a brown oil (173 mg, 70%) over two steps. ESIMS m/z=296.1 (M+1).

Example 4 (S)-tert-butyl1-(1-methyl-4-amino-1H-pyrazol-5-yl)piperidin-3-ylcarbamate

Following the procedures as described in Example 2 and starting with(S)-tert-butyl piperidin-3-ylcarbamate, (S)-tert-butyl1-(1-methyl-4-amino-1H-pyrazol-5-yl)piperidin-3-ylcarbamate was obtainedas a brown oil (206 mg, 75%) over two steps. ESIMS m/z=296.1 (M+1).

Example 5 (S)-tert-butyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-ylcarbamate

Following the procedures as described in Example 2 and starting with(S)-tert-butyl pyrrolidin-3-ylcarbamate, (S)-tert-butyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-ylcarbamate wasobtained as a brown oil (162 mg, 62%) over two steps. ESIMS m/z=282.1(M+1).

Example 6 tert-butyl4-((4-amino-1-methyl-1H-pyrazol-5-yloxy)methyl)piperidine-1-carboxylate

To a 50 mL round bottom flask was added5-chloro-1-methyl-4-nitro-1H-pyrazole (100 mg, 0.60 mmol), tert-butyl4-(hydroxymethyl)piperidine-1-carboxylate (200 mg, 0.93 mmol) and DMF(10 mL). NaH (37 mg, 1.55 mmol) was added slowly and the mixture wasstirred for 1 h. The mixture concentrated and purified via flashchromatography, heptane/ethyl acetate 20% to 80% to afford an oil (150mg, 70%).

To a 50 mL round bottom flask was added the nitro compound (150 mg, 0.44mmol), iron (173 mg, 3.10 mmol), ammonium chloride (199 mg, 3.71 mmol),ethanol (10 mL) and water (1.5 mL). The mixture was stirred for 1 h at60° C. and the reaction was monitored by LCMS. Upon completion of thereaction, the mixture was filtered through a pad of Celite and waswashed with ethyl acetate (30 mL) and a 10% aqueous solution of K₃PO₄(30 mL). The organic layer was washed with water (30 mL), dried overNa₂SO₄ and the organic solvent was distilled off to yield tert-butyl4-((4-amino-1-methyl-1H-pyrazol-5-yloxy)methyl)piperidine-1-carboxylateas a brown oil with a purity of >98% (135 mg, 99%). ESIMS m/z=311.1(M+1).

Example 7 (R)-tert-butyl1-(1-methyl-4-amino-1H-pyrazol-5-yl)piperidin-3-ylcarbamate

Following the procedures as described in Example 2 and starting with(R)-tert-butyl piperidin-3-ylcarbamate, (R)-tert-butyl1-(1-methyl-4-amino-1H-pyrazol-5-yl)piperidin-3-ylcarbamate was obtainedas a brown oil (187 mg, 68%) over two steps. ESIMS m/z=296.1 (M+1).

Example 8 tert-butyl4-(4-amino-1-methyl-1H-pyrazol-5-yloxy)piperidine-1-carboxylate

Following the procedures as described in Example 6 and starting withtert-butyl 4-hydroxypiperidine-1-carboxylate, tert-butyl4-(4-amino-1-methyl-1H-pyrazol-5-yloxy)piperidine-1-carboxylate wasobtained as a brown oil (102 mg, 50%) over two steps. ESIMS m/z=297.1(M+1)

Example 9 (R)-tert-butyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-ylcarbamate

Following the procedures as described in Example 2 and starting with(R)-tert-butyl pyrrolidin-3-ylcarbamate, (R)-tert-butyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-ylcarbamate wasobtained as a brown oil (159 mg, 61%) over two steps. ESIMS m/z=282.1(M+1).

Example 10 tert-butyl4-((4-amino-1-methyl-1H-pyrazol-5-ylamino)methyl)piperidine-1-carboxylate

Following the procedures as described in Example 2 and starting withtert-butyl 4-(aminomethyl)piperidine-1-carboxylate, tert-butyl4-((4-amino-1-methyl-1H-pyrazol-5-ylamino)methyl)piperidine-1-carboxylatewas obtained as a brown oil (124 mg, 43%) over two steps. ESIMSm/z=310.1 (M+1).

Example 11 (S)-tert-butyl(1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-yl)methylcarbamate

Following the procedures as described in Example 2 and starting with(R)-tert-butyl pyrrolidin-3-ylmethylcarbamate, (S)-tert-butyl(1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-yl)methylcarbamate wasobtained as a brown oil (230 mg, 84%) over two steps. ESIMS m/z=296.1(M+1)

Example 12 (R)-tert-butyl(1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-yl)methylcarbamate

Following the procedures as described in Example 2 and starting with(S)-tert-butyl pyrrolidin-3-ylmethylcarbamate, (R)-tert-butyl(1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-yl)methylcarbamate wasobtained as a brown oil (200 mg, 73%) over two steps. ESIMS m/z=296.1(M+1).

Example 13 tert-butyl(1-(4-amino-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate

Following the procedures as described in Example 2 and starting withtert-butyl piperidin-4-ylmethylcarbamate, tert-butyl(1-(4-amino-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate was obtainedas a brown oil (270 mg, 98%) over two steps. ESIMS m/z=310.1 (M+1).

Example 14 (S)-tert-butyl(1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-3-yl)methylcarbamate

Following the procedures as described in Example 2 and starting with(R)-tert-butyl piperidin-3-ylmethylcarbamate, (S)-tert-butyl(1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-3-yl)methylcarbamate wasobtained as a brown oil (270 mg, 98%) over two steps. ESIMS m/z=310.1(M+1).

Example 15 (R)-tert-butyl(1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-3-yl)methylcarbamate

Following the procedures as described in Example 2 and starting with(S)-tert-butyl piperidin-3-ylmethylcarbamate, (R)-tert-butyl(1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-3-yl)methylcarbamate wasobtained as a brown oil (268 mg, 98%) over two steps. ESIMS m/z=310.1(M+1)

Example 16 (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate

Following the procedures as described in Example 2 and starting with(R)-benzyl azepan-4-ylcarbamate, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate was obtained asa brown oil (191 mg, 60%) over two steps. ESIMS m/z=344.1 (M+1).

Example 17 (S)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate

Following the procedures as described in Example 2 and starting with(S)-benzyl azepan-4-ylcarbamate, (S)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate was obtained asa brown oil (220 mg, 63%) over two steps. ESIMS m/z=344.1 (M+1).

Example 18 tert-butyl3-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-ylcarbamate

Following the procedures as described in Example 2 and startingtert-butyl 3-azabicyclo[3.1.0]hexan-6-ylcarbamate, tert-butyl3-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-ylcarbamatewas obtained as a brown oil (130 mg, 48%) over two steps. ESIMSm/z=294.1 (M+1).

Example 19 ethyl 2-amino-2-cyanoacetate

To a stirred solution of (E)-ethyl 2-cyano-2-(hydroxyimino)acetate (20g, 0.14 mol) in water (250 mL) was added a saturated solution of NaHCO₃in water (160 mL), followed by the addition of Na₂S₂O₄ (60 g, 0.423mol). The reaction mixture was warmed up to 35° C. and stirred foradditional 2 hr. It was then saturated with NaCl (150 g) and extractedwith DCM (3×350 mL). Combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo to give ethyl2-amino-2-cyanoacetate as a red oil (7.8 g, 43%) that was used at thenext step without additional purification. ¹H-NMR (CDCl₃, 500 MHz) δ(ppm): 4.45 (s, 1H), 4.34 (q, J=7.0 Hz, 2H), 1.36 (t, J=7.0 Hz, 3H); MS(ESI) m/z: 129 [M+H⁺].

Example 20 ethyl 2-benzamido-2-cyanoacetate

To a stirred solution of compound ethyl 2-amino-2-cyanoacetate (0.64 g,5 mmol) in DCM (15 mL) was added a saturate solution of NaHCO₃ in water(15 mL). With vigorously stirring, benzoyl chloride (0.84 g, 6 mmol) wasadded. The reaction mixture was stirred at ambient temperature foradditional 30 min at which time it was extracted with DCM (3×15 mL).Combined organic layers were washed with brine (20 mL) and dried overNa₂SO₄, filtered, concentrated in vacuo. Resulted residue was purifiedby silica gel column chromatography (5:1 PE/EtOAc) to afford ethyl2-benzamido-2-cyanoacetate (0.25 g, 22%) as white solid: ¹H-NMR (CDCl₃,500 MHz) δ (ppm): 7.83-7.85 (m, 2H), 7.59 (t, J=7.5 Hz, 1H), 7.49 (t,J=7.5 Hz, 2H), 7.02 (d, J=7.0 Hz, 1H), 5.72 (d, J=7.5 Hz, 1H), 4.40 (q,J=7.5 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 233 [M+H⁺].

Example 21 ethyl 5-amino-2-phenylthiazole-4-carboxylate

To a stirred solution of compound ethyl 2-benzamido-2-cyanoacetate (0.46g, 2 mmol) in pyridine (20 mL) was added Lawesson's reagent (0.81 g, 2mmol). The reaction mixture was heated at reflux for 15 hr. It was thenconcentrated and diluted with EtOAc (40 mL). The diluted mixture waswashed with water (3×20 mL), brine (10 mL), dried over Na₂SO₄, filtered,and concentrated in vacuo. The residue was purified by silica gel columnchromatography (10:1 PE/EtOAc) to afford ethyl5-amino-2-phenylthiazole-4-carboxylate (0.2 g, 40%) as yellow solid:¹H-NMR (CDCl₃, 500 MHz) δ (ppm): 7.80 (d, J=6.5 Hz, 1H), 7.36-7.41 (m,3H), 4.43 (q, J=7.0 Hz, 2H), 1.44 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 249[M+H⁺].

Example 22 ethyl5-(tert-butoxycarbonylamino)-2-phenylthiazole-4-carboxylate

To a solution of compound ethyl 5-amino-2-phenylthiazole-4-carboxylate(248 mg, 1 mmol) in CH₃CN (10 mL) was added DMAP (6 mg, 0.05 mmol)followed by (Boc)₂O (262 mg, 1.2 mmol). The reaction mixture wasmaintained at ambient temperature for additional 30 min. The mixture wasthen evaporated in vacuo to give ethyl5-(tert-butoxycarbonylamino)-2-phenylthiazole-4-carboxylate as a redsolid (340 mg, 95%) that was used at the next step without furtherpurification.

Example 23 5-(tert-butoxycarbonylamino)-2-phenylthiazole-4-carboxylicacid

To a solution of compound ethyl5-(tert-butoxycarbonylamino)-2-phenylthiazole-4-carboxylate (348 mg, 1mmol) in MeOH/H₂O (10 mL, 1:1) was added LiOH.H₂O (20 mg, 5 mmol). Thereaction mixture was heated at 50-55° C. until starting materialdisappeared from TLC. It was cooled at about 0-4° C. and conc. HCl addeddropwise until pH of about 5. The resulted mixture was then extractedwith DCM (3×20 mL). Combined organic layers were washed with brine (2×20mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residuewas purified by silica gel column chromatography (50:1 DCM:MeOH) to givethe 5-(tert-butoxycarbonylamino)-2-phenylthiazole-4-carboxylic acid(0.22 g, 68%) as white solid: ¹H-NMR (CDCl₃, 500 MHz) δ (ppm): 9.69 (s,1H), 7.89-7.91 (m, 2H), 7.46-7.47 (m, 3H), 1.57 (s, 9H); MS (ESI) m/z:321 [M+H⁺]

Example 245-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylicacid

Following procedures from Examples 19-23 and shown in FIG. 2,2-fluorobenzoyl chloride was converted to5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylicacid: ¹H-NMR (CDCl₃, 500 MHz) δ (ppm): 9.70 (s, 1H), 8.19-8.23 (m, 1H),7.42-7.45 (m, 1H), 7.20-7.30 (m, 2H), 1.57 (s, 9H); MS (ESI) m/z: 339[M+H⁺]

Example 255-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid

Following procedures from Examples 19-23 and shown in FIG. 2,2,6-difluorobenzoyl chloride was converted to5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid: ¹H-NMR (CD₃OD, 500 MHz) δ (ppm): 7.42-7.46 (m, 1H), 7.06 (t, J=8.5Hz, 2H), 1.47 (s, 9H); MS (ESI) m/z: 355 [M+H]⁺.

Example 265-(tert-butoxycarbonylamino)-2-(2-chlorophenyl)thiazole-4-carboxylicacid

Following procedures from Examples 19-23 and shown in FIG. 2,2-chlorobenzoyl chloride was converted to5-(tert-butoxycarbonylamino)-2-(2-chlorophenyl)thiazole-4-carboxylicacid: ¹H-NMR (DMSO, 500 MHz) δ (ppm): 13.57 (s, 1H), 10.05 (s, 1H),8.14-8.17 (m, 1H), 7.63-7.65 (m, 1H), 7.49-7.51 (m, 2H), 1.53 (s, 9H);MS (ESI) m/z: 355 [M+H⁺].

Example 272-(5-bromo-2-fluorophenyl)-5-(tert-butoxycarbonylamino)thiazole-4-carboxylicacid

Following procedures from Examples 19-23 and shown in FIG. 2,5-bromo-2-fluorobenzoyl chloride was converted to2-(5-bromo-2-fluorophenyl)-5-(tert-butoxycarbonylamino)thiazole-4-carboxylicacid: ¹H-NMR (CDCl₃, 500 MHz) δ (ppm): 9.70 (s, 1H), 8.32-8.34 (m, 1H),7.49-7.52 (m, 1H), 7.09-7.13 (m, 1H), 1.57 (s, 9H); MS (ESI) m/z: 418[M+H⁺].

Example 282-(5-bromo-2-chlorophenyl)-5-(tert-butoxycarbonylamino)thiazole-4-carboxylicacid

Following procedures from Examples 19-23 and shown in FIG. 2,5-bromo-2-chlorobenzoyl chloride was converted to2-(5-bromo-2-chlorophenyl)-5-(tert-butoxycarbonylamino)thiazole-4-carboxylicacid: ¹H-NMR (CDCl₃, 500 MHz) δ (ppm): 9.70 (s, 1H), 8.31 (d, J=2.5 Hz,1H), 7.47 (dd, J=2.5 Hz, J=8.5 Hz, 1H), 7.35 (d, J=9.0 Hz, 1H), 1.57 (s,9H); MS (ESI) m/z: 433 [M+H⁺].

Example 292-(3-bromophenyl)-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid

Following procedures from Examples 19-23 and shown in FIG. 2,3-bromobenzoyl chloride was converted to2-(3-bromophenyl)-5-(tert-butoxycarbonylamino)thiazole-4-carboxylicacid: ¹H-NMR (CDCl₃, 500 MHz) δ (ppm): 9.68 (s, 1H), 8.08 (s, 1H), 7.78(d, J=8.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.32 (t, J=8.0 Hz, 1H), 1.57(s, 9H); MS (ESI) m/z: 399 [M+H⁺]

Example 302-(4-bromo-2-fluorophenyl)-5-(tert-butoxycarbonylamino)thiazole-4-carboxylicacid

Following procedures from Examples 19-23 and shown in FIG. 2,4-bromo-2-fluorobenzoyl chloride was converted to2-(4-bromo-2-fluorophenyl)-5-(tert-butoxycarbonylamino)thiazole-4-carboxylicacid: ¹H-NMR (CDCl₃, 500 MHz) δ (ppm): 9.67 (s, 1H), 8.07 (t, J=8.0 Hz,1H), 7.42 (d, J=9.5 Hz, 1H), 1.57 (s, 9H); MS (ESI) m/z: 417 [M+H⁺]

Example 315-(tert-butoxycarbonylamino)-2-(yridine-2-yl)thiazole-4-carboxylic acid

To a solution of picolinic acid (1.23 g, 10 mmol), EDC.HCl (1.91 g, 10mmol) and HOBT (1.35 g, 10 mmol) in THF (80 mL) was added DIPEA (3.6 g,30 mmol) at ambient temperature. The reaction mixture was maintained atthe same temperature for 1 hr at which time a solution of ethyl2-amino-2-cyanoacetate (1.28 g, 10 mmol) in THF (5 mL) was added. Thereaction mixture was stirred at ambient temperature for additional 6 hr.It was then concentrated, and the residue was purified by silica gelcolumn chromatography (5:1 PE/EtOAc) to give ethyl2-cyano-2-(picolinamido)acetate (0.7 g, 30%) as yellow solid.

Following procedures from Examples 19-23 and shown in FIG. 2, ethyl2-cyano-2-(picolinamido)acetate was converted to5-(tert-butoxycarbonylamino)-2-(yridine-2-yl)thiazole-4-carboxylic acid:¹H-NMR (CDCl₃, 500 MHz) δ (ppm): 9.72 (s, 1H), 8.61 (d, J=4.5 Hz, 1H),8.09 (d, J=8.0 Hz, 1H), 7.81 (t, J=7.5 Hz, 1H), 7.34 (dd, J=5.5 Hz,J=7.0 Hz, 1H), 1.57 (s, 9H); MS (ESI) m/z: 322 [M+H⁺].

Example 32 5-(tert-butoxycarbonylamino)-2-isopropylthiazole-4-carboxylicacid

Following procedures from Examples 19-23 and shown in FIG. 2, isobutyrylchloride was converted to5-(tert-butoxycarbonylamino)-2-isopropylthiazole-4-carboxylic acid:¹H-NMR (CDCl₃, 500 MHz) δ (ppm): 9.54 (s, 1H), 3.16-3.21 (m, 1H), 1.54(s, 9H), 1.37 (d, J=7.0 Hz, 6H); MS (ESI) m/z: 287 [M+H⁺].

Example 335-(tert-butoxycarbonylamino)-2-cyclohexylthiazole-4-carboxylic acid

Following procedures from Examples 19-23 and shown in FIG. 2,cyclohexanecarboxylic acid chloride was converted to5-(tert-butoxycarbonylamino)-2-cyclohexylthiazole-4-carboxylic acid:¹H-NMR (CDCl₃, 500 MHz) δ (ppm): 9.53 (s, 1H), 2.84-2.89 (m, 1H),2.08-2.12 (m, 2H), 1.84 (dd, J=3.5 Hz, J=10.0 Hz, 2H), 1.73 (d, J=13.0Hz, 1H), 1.53 (s, 9H), 1.35-1.50 (m, 4H), 1.25-1.27 (m, 1H); MS (ESI)m/z: 327 [M+H⁺].

Example 34 5-(tert-butoxycarbonylamino)-2-o-tolylthiazole-4-carboxylicacid

Following procedures from Examples 19-23 and shown in FIG. 2,2-methylbenzoyl chloride was converted to5-(tert-butoxycarbonylamino)-2-o-tolylthiazole-4-carboxylic acid: ¹H-NMR(CD₃OD, 500 MHz) δ (ppm): 7.34 (s, 1H), 7.13-7.22 (m, 3H), 2.32 (s, 3H),1.43 (s, 9H); MS (ESI) m/z: 335 [M+H⁺].

Example 355-(tert-butoxycarbonylamino)-2-(2-methoxyphenyl)thiazole-4-carboxylicacid

Following procedures from Examples 19-23 and shown in FIG. 2,2-methoxybenzoyl chloride was converted to5-(tert-butoxycarbonylamino)-2-(2-methoxyphenyl)thiazole-4-carboxylicacid: ¹H-NMR (CD₃OD, 500 MHz) δ (ppm): 9.63 (s, 1H), 8.27 (d, J=7.5 Hz,1H), 7.42 (t, J=8.0 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H), 7.04 (d, J=9.0 Hz,1H), 1.57 (s, 9H); MS (ESI) m/z: 351 [M+H⁺]

Example 365-(tert-butoxycarbonylamino)-2-(2-(trifluoromethyl)phenyl)thiazole-4-carboxylicacid

Following procedures from Examples 19-23 and shown in FIG. 2,2-(trifluoromethyl)benzoyl chloride was converted to5-(tert-butoxycarbonylamino)-2-(2-(trifluoromethyl)phenyl)thiazole-4-carboxylicacid: ¹H-NMR (CD₃OD, 500 MHz) δ (ppm): 7.76 (d, J=7.5 Hz, 1H), 7.58-7.64(m, 3H), 1.46 (s, 9H); MS (ESI) m/z: 389 [M+H⁺].

Example 37 5-(tert-butoxycarbonylamino)-2-methylthiazole-4-carboxylicacid

Following procedures from Examples 19-23 and shown in FIG. 2, acetylchloride was converted to5-(tert-butoxycarbonylamino)-2-methylthiazole-4-carboxylic acid: ¹H-NMR(CDCl₃, 500 MHz) δ (ppm): 9.62 (s, 1H), 2.62 (s, 3H), 1.54 (s, 9H); MS(ESI) m/z: 259 [M+H⁺]

Example 38 5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid

Under N₂, HCOOH (2.44 g, 53 mmol) was added to Ac₂O (6.48 g, 63.6 mmol)at 0° C. After it was allowed to warm to ambient temperature thereaction was heated at 50° C. for 15 hr. It was allowed to cool toambient temperature. This mixed acid anhydride was then added dropwiseto a solution of ethyl 2-amino-2-cyanoacetate (128 mg, 1 mmol) in dryTHF (5 mL) at 0° C. After the cooling bath was removed, the reaction wasmaintained at ambient temperature for additional 1 hr. The reactionmixture was concentrated and purified by silica gel columnchromatography (5:1 PE/EtOAc) to afford ethyl 2-cyano-2-formamidoacetate(110 mg, 70%) as a white solid.

Following procedures from Examples 19-23 and shown in FIG. 2, ethyl2-cyano-2-formamidoacetate was converted to5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid: ¹H-NMR (CDCl₃,500 MHz) δ (ppm): 9.70 (s, 1H), 8.29 (s, 1H), 1.55 (s, 9H); MS (ESI)m/z: 245 [M+H⁺]

Example 39 2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylicacid

To a solution of 5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid(1.72 g, 10 mmol) in DCM (50 mL) was added in three portions NBS (1.95g, 11 mmol); the reaction mixture was stirred at ambient temperature for1 h. Reaction was concentrated in vacuo; resulted residue was purifiedby silica gel column chromatography (6:1 Pet-ether-EtOAc) to afford2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid (1.75 g,70%) as white solid: ¹H-NMR (CDCl₃, 500 MHz) δ (ppm): 13.65 (s, 1H),10.03 (s, 1H), 1.49 (s, 9H). MS (ESI) m/z: 324 [M+H⁺]

Example 405-(tert-butoxycarbonylamino)-2-(2,5-difluorophenyl)thiazole-4-carboxylicacid

Following procedures from Examples 19-23 and shown in FIG. 2,2,5-difluorobenzoyl chloride was converted to5-(tert-butoxycarbonylamino)-2-(2,5-difluorophenyl)thiazole-4-carboxylicacid: ¹H-NMR (CDCl₃, 500 MHz) δ (ppm): 9.68 (s, 1H), 7.87-7.91 (m, 1H),7.15-7.26 (m, 1H), 7.08-7.13 (m, 1H), 1.57 (s, 9H); MS (ESI) m/z: 357[M+H⁺]

Example 415-(tert-butoxycarbonylamino)-2-(2,4-difluorophenyl)thiazole-4-carboxylicacid

Following procedures from Examples 19-23 and shown in FIG. 2,2,4-difluorobenzoyl chloride was converted to5-(tert-butoxycarbonylamino)-2-(2,4-difluorophenyl)thiazole-4-carboxylicacid: ¹H-NMR (CDCl₃, 500 MHz) δ (ppm): 9.66 (s, 1H), 8.16-8.21 (m, 1H),6.95-7.04 (m, 2H), 1.62 (s, 9H); MS (ESI) m/z: 357 [M+H⁺]

Example 425-(tert-butoxycarbonylamino)-2-(2,3-difluorophenyl)thiazole-4-carboxylicacid

Following procedures from Examples 19-23 and shown in FIG. 2,2,3-difluorobenzoyl chloride was converted to5-(tert-butoxycarbonylamino)-2-(2,3-difluorophenyl)thiazole-4-carboxylicacid: ¹H-NMR (CD₃OD, 400 MHz) δ (ppm): 7.45 (s, 1H), 7.07-7.16 (m, 2H),1.42 (s, 9H); MS (ESI) m/z: 357 [M+H⁺].

Example 43 2-benzyl-5-(tert-butoxycarbonylamino)thiazole-4-carboxylicacid

Following procedures from Examples 19-23 and shown in FIG. 2,2-phenylacetyl chloride was converted to2-benzyl-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid: ¹H-NMR(CDCl₃, 500 MHz) δ (ppm): 9.63 (s, 1H), 7.27-7.35 (m, 5H), 4.25 (s, 2H),1.50 (s, 9H); MS (ESI) m/z: 335 [M+H⁺].

Example 445-(tert-butoxycarbonylamino)-2-(quinolin-7-yl)thiazole-4-carboxylic acid

Following procedures from Examples 19-23 and shown in FIG. 2,quinoline-7-carbonyl chloride was converted to5-(tert-butoxycarbonylamino)-2-(quinolin-7-yl)thiazole-4-carboxylicacid: ¹H-NMR (DMSO, 500 MHz) δ (ppm): 10.14 (s, 1H), 9.11 (d, J=5 Hz, 1h), 8.68 (s, 1H), 8.55 (s, 1H), 8.21-8.25 (m, 2H), 7.75-7.77 (m, 1H),1.54 (s, 9H); MS (ESI) m/z: 372 [M+H⁺]

Example 455-(tert-butoxycarbonylamino)-2-(imidazo[1,2-a]yridine-2-yl)thiazole-4-carboxylicacid

Following procedures from Examples 19-23 and shown in FIG. 2,imidazo[1,2-a]pyridine-2-carbonyl chloride was converted to5-(tert-butoxycarbonylamino)-2-(imidazo[1,2-a]yridine-2-yl)thiazole-4-carboxylicacid: ¹H-NMR (DMSO, 500 MHz) δ (ppm): 10.12 (s, 1H), 8.58 (d, 5 Hz, 1H),8.45 (s, 1H), 7.61 (d, 5 Hz, 1H), 7.31-7.34 (m, 1H), 6.97-6.99 (m, 1H),1.53 (s, 9H); MS (ESI) m/z: 361 [M+H⁺].

Example 465-(tert-butoxycarbonylamino)-2-tert-butylthiazole-4-carboxylic acid

Following procedures from Examples 19-23 and shown in FIG. 2, pivaloylchloride was converted to5-(tert-butoxycarbonylamino)-2-tert-butylthiazole-4-carboxylic acid:¹H-NMR (CDCl₃, 500 MHz) δ (ppm): 9.55 (s, 1H), 1.55 (s, 9H), 1.42 (s,9H); MS (ESI) m/z: 301 [M+H⁺].

Example 475-(tert-butoxycarbonylamino)-2-(3-chlorophenyl)thiazole-4-carboxylicacid

Following procedures from Examples 19-23 and shown in FIG. 2,3-chlorobenzoyl chloride was converted to5-(tert-butoxycarbonylamino)-2-(3-chlorophenyl)thiazole-4-carboxylicacid: ¹H-NMR (DMSO, 500 MHz) δ (ppm): 9.67 (s, 1H), 7.91 (s, 1H), 7.72(d, J=7 Hz, 1H), 7.38-7.40 (m, 2H), 1.56 s, 9H); MS (ESI) m/z: 355[M+H⁺].

Example 485-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)thiazole-4-carboxylicacid

Following procedures from Examples 19-23 and shown in FIG. 2,4-chlorobenzoyl chloride was converted to5-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)thiazole-4-carboxylicacid: ¹H-NMR (DMSO, 500 MHz) δ (ppm): 9.66 (s, 1H), 7.81 (d, J=8.5 Hz,2H), 7.42 (d, J=8.5 Hz, 2H), 1.56 (s, 9H); MS (ESI) m/z: 355 [M+H⁺].

Example 49 5-amino-N-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide

Following the procedures as described in Example 113,1-methyl-1H-pyrazol-4-amine,5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid were reacted togive 5-amino-N-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide as awhite solid (13 mg, 32%) over two steps. ESIMS m/z=336.1 (M+1)

Example 50 tert-butyl3-(4-amino-1-methyl-1H-pyrazol-5-yl)phenylcarbamate

To a 10 mL microwave vial was added5-chloro-1-methyl-4-nitro-1H-pyrazole (150 mg, 0.93 mmol),3-(tert-butoxycarbonylamino)phenylboronic acid (440 mg, 1.86 mmol),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (152 mg,0.019 mmol), a 1:1 M solution of Na₂CO₃/KOAc (1 mL) and acetonitrile (4mL). The mixture was irradiated to 130° C. with a microwave for 40 minand the mixture was cooled, concentrated and purified via flashchromatography, heptane/ethyl acetate 20% to 95% to afford a yellow oil.To a 50 mL round bottom flask was added the nitro compound (120 mg, 0.90mmol), iron (156 mg, 2.8 mmol), ammonium chloride (200 mg, 3.7 mmol),ethanol (10 mL) and water (1.5 mL). The mixture was stirred for 1 h andthe reaction was monitored by LCMS. Upon completion of the reaction, themixture was filtered through a pad of Celite and was washed with ethylacetate (30 mL) and a 10% aqueous solution of K₃PO₄ (30 mL). The organiclayer was washed with water (30 mL), dried over Na₂SO₄ and the organicsolvent was distilled off to yield tert-butyl3-(4-amino-1-methyl-1H-pyrazol-5-yl)phenylcarbamate as a brown oil witha purity of >98% (120 mg, 45%) over two steps. ESIMS m/z=289.1 (M+1)

Example 51 1-methyl-5-o-tolyl-1H-pyrazol-4-amine

Following the procedures as described in Example 2 and starting witho-tolylboronic acid, 1-methyl-5-o-tolyl-1H-pyrazol-4-amine was obtainedas a brown oil (148 mg, 85%) over two steps. ESIMS m/z=188.1 (M+1)

Example 512-(4-Cyclopropyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step 1: Preparation of 3-fluoro-4-nitrophenyl trifluoromethanesulfonate

To a stirred solution of 3-fluoro-4-nitrophenol (10.00 g, 63.65 mmol)and trifluoromethanesulfonic anhydride (20.0 mL, 119 mmol, 1.87 eq.) inanhydrous DCM (100.0 mL) at 0° C. was added dropwise triethylamine(33.27 mL, 238.7 mmol, 3.75 eq.). The resultant brown reaction mixturewas stirred at 0° C. for 2 h and then stirred at ambient temperature for16 h. The reaction mixture was slowly quenched with water and extractedwith DCM (3×100 mL). The combined organic layers were washed with brine(1×), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The crude oil was purified via flash column chromatographyeluted with 0 to 65% DCM/hexane to give 15.67 g (85.1%) of3-fluoro-4-nitrophenyl trifluoromethanesulfonate as an oil. ¹H NMR (500MHz, CDCl₃) δ 8.23 (t, J=8.52 Hz, 1H), 7.34-7.27 (m, 2H).

Step 2: Preparation of 4-cyclopropyl-2-fluoro-1-nitrobenzene

A mixture of 3-fluoro-4-nitrophenyl trifluoromethanesulfonate (7.15 g,24.73 mmol), cyclopropylboronic acid (2.55 g, 29.67 mmol),[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complexedwith dichloromethane (1:1) (1.62 g, 1.98 mmol), and 2M cesium carbonatein water (19.8 mL, 39.56 mmol) in toluene (39.5 mL) was degassed for 20min. The reaction mixture was stirred at 90° C. under N₂ for 2.5 h. Thereaction was cooled to RT, diluted with ethyl acetate (200 mL), andfiltered through a pad of Celite. The filtrate was washed with brine,dried over Na₂SO₄, filtered, and concentrated under reduced pressure.The crude residue was purified via flash column chromatography elutedwith 0 to 75% DCM/hexane to give 4.11 g (91.7%) of4-cyclopropyl-2-fluoro-1-nitrobenzene as an oil. ¹H NMR (400 MHz, MeOD)δ 7.98 (dd, J=10.2, 6.6 Hz, 1H), 7.12-7.02 (m, 2H), 2.11-1.97 (m, 1H),1.20-1.11 (m, 2H), 0.89-0.82 (m, 2H).

Step 3: Preparation of 4-cyclopropyl-2-fluoroaniline

A mixture of 4-cyclopropyl-2-fluoro-1-nitrobenzene (3.36 g, 18.55 mmol),powdered iron (4.35 g, 77.9 mmol), and 2M ammonium chloride in water(19.8 mL) and 3:2:1 v/v EtOH:THF:H₂O (86 mL) was stirred at reflux underN₂ for 17 h. The reaction mixture was cooled to RT and filtered througha pad of Celite. The Celite pad was rinsed well with ethyl acetate (˜50mL). Saturated aqueous NaHCO₃ solution was slowly added to the filtrateto neutalize the reaction mixture. The reaction mixture was extractedwith ethyl acetate (3×200 mL). The combined organic layers were washedwith water and brine, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The crude residue was purified via flash columnchromatography eluted with 0 to 75% ethyl acetate/hexane to give 2.80 g(99%) of an orange oil, which solidified at 20° C. ¹H NMR (400 MHz,CDCl₃) δ 6.75-6.63 (m, 3H), 3.57 (s, 2H), 1.87-1.72 (m, 1H), 0.93-0.83(m, 2H), 0.64-0.51 (m, 2H); MS (ESI) m/z: 152.3 [M+H⁺].

Step 4: Preparation of 4-cyclopropyl-2-fluoro-1-iodobenzene

To a stirred mixture of 4-cyclopropyl-2-fluoroaniline (1.63 g, 10.78mmol) in water (20 mL) at 0° C. was added concentrated sulfuric acid(8.6 mL, 15.0 eq.) dropwise, while keeping the temperature constant at0° C. A solution of sodium nitrite (781.0 mg, 11.32 mmol, 1.05 eq.) inwater (2.7 mL) was added and stirred for 5 minutes. This resultingreaction mixture was then added to a solution of potassium iodide (3.76g, 22.64 mmol, 2.1 eq.) in water (9.7 mL), and the reaction mixture wasstirred at 60° C. for 3 h. DCM (400 mL) was added to the cooledreaction. The biphasic layers were separated, and the aqueous layer wasextracted with DCM (2×150 mL). The combined organic layers were washedwith saturated aqueous Na₂S₂O₄, water, and brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The crude residue waspurified via flash column chromatography eluted with 100% heptane togive 2.01 g (71.28%) of 4-cyclopropyl-2-fluoro-1-iodobenzene as a clearoil. ¹H NMR (400 MHz, CDCl₃) δ 7.57 (dd, J=8.0, 6.9 Hz, 1H), 6.76 (dd,J=9.4, 1.9 Hz, 1H), 6.64 (dd, J=8.2, 1.9 Hz, 1H), 1.94-1.77 (m, 1H),1.09-0.95 (m, 2H), 0.79-0.56 (m, 2H).

Step 5: In a high pressure tube was placed4-cyclopropyl-2-fluoro-1-iodobenzene (1.32 g, 5.04 mmol), bispinacolester boronate (1.53 g, 6.04 mmol), potassium acetate (1.98 g, 20.15mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(368.5 mg, 0.50 mmol), and N,N-dimethylformamide (35 mL). The reactionmixture was degassed with N₂ for 15 minutes. The vessel was sealed andthe reaction mixture was stirred at 90° C. for 16 h. The cooled reactionmixture was diluted with ethyl acetate (75 mL) and water (25 mL) andthen filtered through a pad of Celite. The biphasic layers wereseparated and the organic layer was washed with water and brine, driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Thecrude residue was purified via flash column chromatography eluted with 0to 75% EA/heptane to give 859.0 mg (65.1%) of2-(4-cyclopropyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneas a clear oil. ¹H NMR (400 MHz, CDCl₃) δ 7.58 (s, 1H), 6.83 (d, J=7.7Hz, 1H), 6.68 (d, J=10.8 Hz, 1H), 1.91-1.81 (m, 1H), 1.33 (s, 12H), 0.98(dd, J=8.3, 2.0 Hz, 2H), 0.74-0.66 (m, 2H)

Example 53((R)-1-{4-[(2-Bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl)-amino]-2-methyl-2H-pyrazol-3-yl}-perhydro-azepin-4-yl)-carbamicacid benzyl ester

To a stirred solution of2-bromo-5-(isopropoxycarbonylamino)-thiazole-4-carboxylic acid (650.0mg, 2.01 mmol) and[(R)-1-(4-amino-2-methyl-2H-pyrazol-3-yl)-azepan-4-yl]-carbamic acidbenzyl ester (828.9 mg, 2.41 mmol, 1.2 eq.) in anhydrousN,N-dimethylformamide (22 mL) was added HATU (1.07 g, 2.81 mmol, 1.4eq.) followed by N,N-diisopropylethylamine (0.88 mL, 5.03 mmol, 2.5eq.), and the reaction mixture was stirred at RT under N₂ for 7 days.The reaction mixture was diluted with ethyl acetate (150 mL). Theorganic layer was washed with 50% brine/water, water and brine, driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Thecrude was purified via flash column chromatography eluted with 45 to100% ethyl acetate/heptane to give 1.30 g (79.7%) of((R)-1-{4-[(2-Bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl)-amino]-2-methyl-2H-pyrazol-3-yl}-perhydro-azepin-4-yl)-carbamicacid benzyl ester as a tacky gel. ¹H NMR (400 MHz, CDCl₃) δ 10.28 (s,1H), 8.39 (s, 1H), 7.74 (s, 1H), 7.33 (s, 5H), 5.09 (s, 2H), 4.98 (s,1H), 3.89 (s, 1H), 3.72 (s, 3H), 3.36-3.21 (m, 2H), 3.16-3.03 (m, 2H),2.19-2.01 (m, 2H), 2.00-1.61 (m, 4H), 1.51 (s, 9H)

Example 54N-(5,5-Difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide

Dess Martin periodinane (2.3 g, 5.4 mmol) was added portionwise to asolution of benzyl 4-azido-5-hydroxyazepane-1-carboxylate (1.3 g, 4.5mmol) in DCM (25 mL). After stirring at room temperature for 18 hr, themixture was diluted with DCM and quenched with aqueous NaHCO₃ (40 mL)followed by aqueous Na₂S₂O₃ (20%, 40 mL). The resulting mixture wasstirred for 20 min. The organic layer was separated, dried over Na₂SO₄and the solvent removed under reduced pressure. Purification via silicagel column chromatography (0-50% EtOAc/isohexane) gave benzyl4-azido-5-oxoazepane-1-carboxylate (1.10 g, 84%) as a clear oil. To asolution of this oil (1.10 g, 3.8 mmol) in DCM (10 mL) was addeddeoxo-Fluor® (50% in THF, 3.5 mL, 9.5 mmol) and the mixture was stirredat room temperature for 18 hr. The mixture was diluted with DCM, cooledin an ice/water bath and quenched by dropwise addition of saturatedaqueous NaHCO₃ (20 mL). Effervescence was observed. The resultingmixture was stirred for 10 min. The organic layer was separated, driedover Na₂SO₄ and the solvent removed under reduced pressure. The crudeproduct was purified via silica gel column chromatography (0-40%EtOAc/isohexane) to give benzyl5-azido-4,4-difluoroazepane-1-carboxylate (0.65 g, 56%) as a clear oil.This oil was dissolved in THF (10 mL) and water (2 mL) andtriphenylphosphine (0.58 g, 2.2 mmol) added. After stirring and heatingat 60° C. for 18 hr, the mixture was concentrated under reducedpressure. The crude product was dissolved in DCM and the organic layerwas washed with water, separated, dried over Na₂SO₄ and the solventremoved under reduced pressure. To the crude product in DCM (20 mL),cooled in a water/ice bath, was added DIPEA (1.1 mL, 6.36 mmol) followedby trifluoroacetic anhydride (0.75 mL, 5.3 mmol) dropwise. The mixturewas allowed to warm to room temperature, stirred for 18 hr and dilutedwith DCM. Water was added and the organic layer was separated, driedover Na₂SO₄ and the solvent was removed under reduced pressure. Theresidue was purified via silica gel column chromatography (0-60%EtOAc/isohexane) to yield benzyl4,4-difluoro5-(2,2,2-trifluoroacetamido)azepane-1-carboxylate (0.59 g,73%) as a clear oil. This trifluoroacetamide (0.57 g, 1.5 mmol) wasdissolved in MeOH (50 mL) and passed through the H-Cube® (Full H₂ Mode,70° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent wasremoved under reduced pressure to give crudeN-(5,5-difluoroazepan-4-yl)-2,2,2-trifluoroacetamide. To a solution ofthe azepane (0.37 g, 1.5 mmol) in EtOH (4 mL) was added5-chloro-1-methyl-4-nitro-1H-pyrazole (0.73 g, 4.5 mmol) and DIPEA (0.65mL, 3.8 mmol). The mixture was heated at 130° C. in a microwave for 6hr. The solvent was removed under reduced pressure and the crude productwas purified via silica gel column chromatography (0-50%EtOAc/isohexane) to yieldN-(5,5-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamideas a pale yellow oil (0.31 g, 56%). ¹H NMR (400 MHz, CDCl₃) δ 8.05 (s,1H), 6.77 (d, J=9.0 Hz, 1H), 4.72-4.58 (m, 1H), 3.80 (s, 3H), 3.55-3.39(m, 2H), 3.33-3.18 (m, 2H), 2.52-2.17 (m, 3H), 2.14-2.04 (m, 1H).

Example 55 tert-Butyl4-(5-(4,4-difluoro-5-(2,2,2-trifluoroacetamido)azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate

A solution ofN-(5,5-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide(0.29 g, 0.78 mmol) in MeOH (20 mL) was passed through the H-Cube® (FullH₂ Mode, 70° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). Thesolvent was removed under reduced pressure to give the crude amine. To asolution of this amine (0.26 g, 0.78 mmol) in DCM (15 mL) was addedDIPEA (0.68 mL, 3.9 mmol), PyBOP (0.61 g, 1.17 mmol) and5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid (0.30 g, 0.86 mmol) and the mixture was stirred at room temperaturefor 18 hr. The mixture was diluted with DCM and washed with water. Theorganic layer was separated, dried over Na₂SO₄ and the solvent removedunder reduced pressure. Purification via silica gel columnchromatography (0-80% EtOAc/isohexane) gave tert-butyl4-(5-(4,4-difluoro-5-(2,2,2-trifluoroacetamido)-azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamateas a white solid (0.37 g, 69%). ¹H NMR (400 MHz, CDCl₃) δ 10.28 (s, 1H),8.71 (s, 1H), 7.82 (s, 1H), 7.42-7.33 (m, 1H), 7.11-7.01 (m, 2H), 6.72(d, J=9.0 Hz, 1H), 4.73-4.57 (m, 1H), 3.77 (s, 3H), 3.51-3.37 (m, 2H),3.36-3.25 (m, 2H), 2.49-2.36 (m, 2H), 2.25-2.03 (m, 2H), 1.55 (s, 9H).

Example 56 3,3-Difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine

A mixture of 5-chloro-1-methyl-4-nitro-1H-pyrazole (0.1 g, 4.5 mmol),3,3-difluoropiperidine hydrochloride (0.14 g, 0.93 mmol) and DIPEA (0.5mL, 2.8 mmol) in EtOH (3 mL) was heated at 130° C. in a microwave for 1hr. Additional DIPEA (0.5 mL, 2.8 mmol) and 3,3-difluoropiperidinehydrochloride (0.29 g, 1.8 mmol) were added and the mixture was heatedat 130° C. in a microwave for 2 hr. The solvent was removed underreduced pressure and the crude product was purified via silica gelcolumn chromatography (0-60% EtOAc/isohexane) to yield3,3-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine as a yellowoil (127 mg, 83%). ¹H NMR (400 MHz, CDCl₃) δ 8.04 (s, 1H), 3.80 (s, 3H),3.41-3.29 (m, 2H), 3.26-3.04 (m, 2H), 2.17-2.03 (m, 2H), 1.97-1.88 (m,2H).

Example 57 tert-Butyl2-(2,6-difluorophenyl)-4-(5-(3,3-difluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

Following the procedure for Example 55, starting with3,3-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine and5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid, gave tert-butyl2-(2,6-difluorophenyl)-4-(5-(3,3-difluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateas a cream solid (57 mg, 20%). ¹H NMR (400 MHz, CDCl₃) δ 10.33 (s, 1H),8.67 (s, 1H), 7.71 (s, 1H), 7.41-7.32 (m, 1H), 7.11-7.01 (m, 2H), 3.76(s, 3H), 3.32 (t, J=11.0 Hz, 2H), 3.19-3.13 (m, 2H), 2.10-1.97 (m, 2H),1.94-1.85 (m, 2H), 1.53 (s, 9H).

Example 58 tert-Butyl3-(methyl(1-methyl-4-nitro-1H-pyrazol-5-yl)amino)propylcarbamate

A mixture of 5-chloro-1-methyl-4-nitro-1H-pyrazole (0.81 g, 5 mmol),tert-butyl 3-aminopropylcarbamate (0.85 g, 4.88 mmol) and DIPEA (1.8 mL,10.5 mmol) in EtOH (5 mL) was heated at 130° C. in the microwave for 90min. On cooling the reaction mixture was concentrated under reducedpressure and the residue purified via silica gel column chromatography(0-100% EtOAc/isohexane) to afford tert-butyl3-(1-methyl-4-nitro-1H-pyrazol-5-ylamino)propylcarbamate as a yellow gum(1.27 g, 85%). A mixture of this gum (0.3 g, 1 mmol), K₂CO₃ (0.41 g, 3mmol) and methyl iodide (0.1 mL, 1.58 mmol) in DMF (5 mL) was stirred at60° C. for 18 hr. More methyl iodide (0.1 mL, 1.58 mmol) was added andstirring at 60° C. was continued for 24 hr. The reaction mixture wascooled and concentrated under reduced pressure. The residue wastriturated in DCM (100 mL), filtered and the filtrate concentrated underreduced pressure. Purification via silica gel column chromatography(0-100% EtOAc/isohexane) gave tert-butyl3-(methyl(1-methyl-4-nitro-1H-pyrazol-5-yl)amino)propylcarbamate as apale yellow gum (0.122 g, 38%). ¹H-NMR (400 MHz, CDCl₃) δ 8.03 (s, 1H),4.60 (s, 1H), 3.77 (s, 3H), 3.20-3.14 (m, 4H), 2.86 (s, 3H), 1.72-1.61(m, 2H), 1.42 (s, 9H).

Example 59 tert-Butyl2-(2,6-difluorophenyl)-4-(5-(tert-butyl-(3-methylamino)propylcarbamoyl-3-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

A solution of tert-butyl3-(methyl(1-methyl-4-nitro-1H-pyrazol-5-yl)amino)propylcarbamate (122mg, 0.39 mmol) in MeOH (15 mL) was passed through the H-Cube® (Full H₂Mode, 50° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). Thesolvent was removed under reduced pressure to afford a red oil (0.12 g).To a solution of this oil in DCM (10 mL) was added5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid (166 mg, 0.47 mmol), PyBOP (0.33 g, 0.64 mmol) and DIPEA (0.5 mL,2.86 mmol) and the mixture was stirred at room temperature for 66 hr.Water (20 ml) was added and stirring continued for 30 min. The layerswere separated and the aqueous layer extracted with DCM. The combinedorganic layers were passed through a phase separation cartridge and thesolvent removed under reduced pressure. Purification via silica gelcolumn chromatography (0-100% EtOAc/isohexane) gave tert-butyl2-(2,6-difluorophenyl)-4-(5-(tert-butyl-(3-methylamino)propylcarbamoyl-3-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateas a white solid (207 mg, 90%). ¹H-NMR (400 MHz, CDCl₃) δ 10.37 (s, 1H),8.74 (s, 1H), 7.87 (s, 1H), 7.42-7.32 (m, 1H), 7.10-7.02 (m, 2H), 4.65(s, 1H), 3.75 (s, 3H), 3.20-3.14 (m, 2H), 3.10 (t, J=7 Hz, 2H), 2.85 (s,3H), 1.76-1.66 (m, 2H), 1.55 (s, 9H), 1.39 (s, 9H).

Example 60 5-Chloro-1-ethyl-4-nitro-1H-pyrazole

Following the procedure for Example 1 starting with1-ethyl-4-nitropyrazole gave 5-chloro-1-ethyl-4-nitro-1H-pyrazole as acolourless solid (1.3 g, 74%). ¹H-NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H),4.26 (q, J=7 Hz, 2H), 1.50 (t, J=7 Hz, 3H).

Example 61 5-Chloro-1-cyclopropylmethyl-4-nitro-1H-pyrazole

Following the procedure for Example 1 starting with1-cyclopropylmethyl-4-nitropyrazole gave5-chloro-1-cyclopropylmethyl-4-nitro-1H-pyrazole as a colourless oil(1.16 g, 56%). ¹H-NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H), 4.07 (d, J=7 Hz,2H), 1.39-1.28 (m, 1H), 0.66-0.59 (m, 2H), 0.50-0.40 (m, 2H).

Example 62 5-Chloro-1-cyclopropyl-4-nitro-1H-pyrazole

Following the procedure for Example 1 starting with1-cyclopropyl-4-nitropyrazole gave5-chloro-1-cyclopropyl-4-nitro-1H-pyrazole as a colourless solid (0.23g, 63%). ¹H-NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H), 3.62-3.54 (m, 1H),1.38-1.28 (m, 2H), 1.25-1.13 (m, 2H).

Example 63 (R)—N-(Azepan-4-yl)-2,2,2-trifluoroacetamide

A solution of (R)-tert-butyl4-(benzyloxycarbonylamino)azepane-1-carboxylate (3.25 g, 0.33 mmol) inMeOH (100 mL) was stirred at room temperature under an atmosphericpressure of hydrogen gas in the presence of 10% Pd/C (1 g) for 1.5 hr.The mixture was filtered through celite and the solvent removed underreduced pressure to afford (R)-tert-butyl4-(2,2,2-trifluoroacetamido)azepane-1-carboxylate as a pale grey oil (2g, 100%). To a stirred solution of this oil (1.8 g, 8.4 mmol) and DIPEA(3 mL, 17.18 mmol) in DCM (100 mL) at room temperature was addedtrifluoroacetic anhydride (1.31 mL, 9.27 mmol) dropwise over 5 min andthe resultant pale yellow solution was stirred for 18 hr. Saturatedaqueous sodium hydrogen carbonate (150 mL) was added and stirringcontinued for 1 hr. The layers were separated, the organics passedthrough a phase separation cartridge and the solvent removed underreduced pressure to give (R)-tert-butyl4-(2,2,2-trifluoroacetamido)azepane-1-carboxylate as a pale yellow oil(2.61 g, 100%). To a solution of this oil (2.6 g, 8.38 mmol) in DCM (50mL) at room temperature was added trifluoracetic acid (25 mL) and themixture stirred for 2 hr. The solvent was removed under reduced pressureand the residue dissolved in DCM and passed through an SCX columnwashing with DCM and MeOH and eluting with 1 N ammonia in MeOH. Thesolvent was removed under reduced pressure to afford(R)—N-(azepan-4-yl)-2,2,2-trifluoroacetamide as a pale yellow oil (1.3g, 74%). ¹H-NMR (400 MHz, CDCl₃) δ 7.83 (s, 1H), 4.44-4.37 (m, 1H),3.13-3.03 (m, 2H), 2.88 (dt, J=13.2, 6.6 Hz, 1H), 2.65-2.55 (m, 1H),2.03-1.79 (m, 3H), 1.75 (s, 1H), 1.69-1.58 (m, 3H).

Example 64 (S)—N-(Azepan-4-yl)-2,2,2-trifluoroacetamide

Following the procedure for Example 510 starting with (S)-tert-butyl4-(benzyloxycarbonylamino)azepane-1-carboxylate gave(S)—N-(azepan-4-yl)-2,2,2-trifluoroacetamide as a pale yellow oil (1.35g, 75% over three steps). ¹H-NMR (400 MHz, CDCl₃) δ 7.86 (s, 1H),4.44-4.37 (m, 1H), 3.15-3.03 (m, 2H), 2.92-2.81 (m, 1H), 2.67-2.55 (m,1H), 2.02-1.81 (m, 4H), 1.76-1.56 (m, 3H).

Example 65N-(1-(1-Ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide

Following the procedure for Example 503 starting with5-chloro-1-ethyl-4-nitro-1H-pyrazole and2,2,2-trifluoro-N-(hexahydro-1H-azepin-4-yl)-acetamide gaveN-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamideas a pale yellow gum (0.136 g, 55%). ¹H-NMR (400 MHz, CDCl₃) δ 8.07 (s,1H), 6.39-6.37 (m, 1H), 4.22-4.19 (m, 1H), 4.12 (q, J=7 Hz, 2H),3.42-3.35 (m, 1H), 3.27-3.18 (m, 3H), 2.25-2.05 (m, 2H), 2.00-1.75 (m,4H), 1.47 (t, J=7 Hz, 3H).

Example 66(R)—N-(1-(1-Ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide

Following the procedure for Example 503 starting with5-chloro-1-ethyl-4-nitro-1H-pyrazole and(R)-2,2,2-trifluoro-N-(hexahydro-1H-azepin-4-yl)-acetamide (0.1 g, 0.476mmol) gave(R)—N-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamideas a pale yellow gum (0.1 g, 60%). ¹H-NMR (400 MHz, CDCl₃) δ 8.07 (s,1H), 6.39-6.36 (m, 1H), 4.23-4.19 (m, 1H), 4.12 (q, J=7 Hz, 2H),3.42-3.35 (m, 1H), 3.27-3.18 (m, 3H), 2.25-2.05 (m, 2H), 2.00-1.75 (m,4H), 1.47 (t, J=7 Hz, 3H).

Example 67(S)—N-(1-(1-Ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide

Following the procedure for Example 503 starting with5-chloro-1-ethyl-4-nitro-1H-pyrazole and(S)-2,2,2-trifluoro-N-(hexahydro-1H-azepin-4-yl)-acetamide gave(S)—N-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamideas a pale yellow gum (0.12 g, 44%). ¹H-NMR (400 MHz, CDCl₃) δ 8.07 (s,1H), 6.42-6.40 (m, 1H), 4.22-4.18 (m, 1H), 4.12 (q, J=7 Hz, 2H),3.42-3.35 (m, 1H), 3.27-3.18 (m, 3H), 2.25-2.05 (m, 2H), 2.00-1.75 (m,4H), 1.47 (t, J=7 Hz, 3H).

Example 68(R)—N-(1-(1-Cyclopropylmethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide

Following the procedure for Example 503 starting with5-chloro-1-cyclopropylmethyl-4-nitro-1H-pyrazole and(R)-2,2,2-trifluoro-N-(hexahydro-1H-azepin-4-yl)-acetamide gave(R)—N-(1-(1-cyclopropylmethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamideas a pale yellow gum (0.98 g, 55%). ¹H-NMR (400 MHz, CDCl₃) δ 8.08 (s,1H), 6.42-6.39 (m, 1H), 4.22-4.14 (m, 1H), 4.00-3.85 (m, 2H), 3.44-3.32(m, 1H), 3.30-3.15 (m, 3H), 2.25-2.05 (m, 2H), 2.00-1.75 (m, 4H),1.30-1.20 (m, 1H), 0.70-0.62 (m, 2H), 0.50-0.35 (m, 2H).

Example 69(R)—N-(1-(1-Cyclopropyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide

Following the procedure for Example 503 starting with5-chloro-1-cyclopropyl-4-nitro-1H-pyrazole and(R)-2,2,2-trifluoro-N-(hexahydro-1H-azepin-4-yl)-acetamide gave(R)—N-(1-(1-cyclopropyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamideas a pale yellow gum (0.105 g, 61%). ¹H-NMR (400 MHz, CDCl₃) δ 7.96 (s,1H), 6.55-6.38 (m, 1H), 4.30-4.15 (m, 1H), 3.65-3.53 (m, 1H), 3.55-3.25(m, 4H), 2.25-2.05 (m, 6H), 1.35-1.05 (m, 4H).

Example 70 tert-Butyl2-(2,6-difluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

A solution ofN-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide(136 mg, 0.39 mmol) in MeOH (15 mL) was passed through the H-Cube® (70bar, 25° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solventwas removed under reduced pressure to afford the crude amine as a purplegum (121 mg). To a solution of this amine in DCM (10 mL) was added5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid (149 mg, 0.42 mmol), HATU (0.43 g, 1.14 mmol) and DIPEA (1 mL, 5.72mmol). The mixture was stirred at room temperature for 18 hr. Water (30ml) was added and stirring continued for 15 min. The layers wereseparated and the aqueous extracted with DCM. The combined organics werepassed through a phase separation cartridge and the solvent removedunder reduced pressure. Purification of the residue via silica gelcolumn chromatography (0-100% EtOAc/isohexane) gave tert-butyl2-(2,6-difluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateas a colourless solid (170 mg, 68%). ¹H-NMR (400 MHz, CDCl₃) δ 10.39 (s,1H), 8.75 (s, 1H), 7.95 (s, 1H), 7.42-7.33 (m, 1H), 7.12-7.02 (m, 2H),6.35 (d, J=8 Hz, 1H), 4.25-4.13 (m, 1H), 4.05 (q, J=7 Hz, 2H), 3.45-3.25(m, 2H), 3.23-3.10 (m, 2H), 2.25-1.65 (m, 6H), 1.56 (s, 9H), 1.45 (t,J=7 Hz, 3H).

Example 71 (R)-tert-Butyl2-(2,6-difluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

Following the procedure for Example 517 starting with(R)—N-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamideand5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid gave (R)-tert-butyl2-(2,6-difluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateas a cream solid (0.148 g, 76%). ¹H-NMR (400 MHz, CDCl₃) δ 10.40 (s,1H), 8.76 (s, 1H), 7.95 (s, 1H), 7.43-7.34 (m, 1H), 7.12-7.02 (m, 2H),6.37 (d, J=8 Hz, 1H), 4.23-4.16 (m, 1H), 4.05 (q, J=7 Hz, 2H), 3.43-3.31(m, 2H), 3.25-3.15 (m, 2H), 2.22-2.05 (m, 2H), 2.03-1.89 (m, 2H),1.89-1.72 (m, 2H), 1.57 (m, 12H).

Example 72 (S)-tert-Butyl2-(2,6-difluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

Following the procedure for Example 517 starting with(S)—N-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamideand5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid gave (S)-tert-butyl2-(2,6-difluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateas a cream solid (151 mg, 66%). ¹H-NMR (400 MHz, CDCl₃) δ 10.40 (s, 1H),8.75 (s, 1H), 7.95 (s, 1H), 7.45-7.34 (m, 1H), 7.12-7.02 (m, 2H), 6.37(d, J=8 Hz, 1H), 4.23-4.16 (m, 1H), 4.05 (q, J=7 Hz, 2H), 3.43-3.31 (m,2H), 3.25-3.15 (m, 2H), 2.22-2.05 (m, 2H), 2.03-1.89 (m, 2H), 1.89-1.72(m, 2H), 1.55 (s, 9H), 1.46 (t, J=7 Hz, 3H).

Example 73 (R)-tert-Butyl2-(2,6-difluorophenyl)-4-(1-cyclopropylmethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

Following the procedure for Example 517 starting with(R)—N-(1-(1-cyclopropylmethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamideand5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid gave (R)-tert-butyl2-(2,6-difluorophenyl)-4-(1-cyclopropylmethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateas a cream solid (136 mg, 77%). ¹H-NMR (400 MHz, CDCl₃) δ 10.39 (s, 1H),8.75 (s, 1H), 7.95 (s, 1H), 7.41-7.36 (m, 1H), 7.10-7.02 (m, 2H), 6.37(d, J=8 Hz, 1H), 4.25-4.10 (m, 1H), 3.90-3.83 (m, 2H), 3.43-3.31 (m,2H), 3.30-3.15 (m, 2H), 2.25-2.05 (m, 2H), 2.03-1.70 (m, 4H), 1.57 (s,9H) 1.35-1.20 (m, 1H), 0.64-0.59 (m, 2H), 0.43-0.38 (m, 2H).

Example 74 (R)-tert-Butyl2-(2,6-difluorophenyl)-4-(1-cyclopropyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

Following the procedure for Example 517 starting with(R)—N-(1-(1-cyclopropyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamideand5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid gave (R)-tert-butyl2-(2,6-difluorophenyl)-4-(1-cyclopropyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateas a cream solid (142 mg, 73%). ¹H-NMR (400 MHz, CDCl₃) δ 10.40 (s, 1H),8.76 (s, 1H), 7.87 (s, 1H), 7.41-7.34 (m, 1H), 7.10-7.00 (m, 2H), 6.39(d, J=8 Hz, 1H), 4.25-4.15 (m, 1H), 3.45-3.36 (m, 3H), 3.35-3.15 (m,2H), 2.25-2.12 (m, 1H), 2.10-1.70 (m, 5H), 1.55 (s, 9H), 1.35-1.15 (m,2H), 1.10-1.00 (m, 2H).

Example 75 (R)-tert-Butyl2-(2-fluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

Following the procedure for Example 506 starting with(R)—N-(1-(1-ethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamideand 5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylicacid gave (R)-tert-butyl2-(2-fluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateas a cream solid (330 mg, 72%). ¹H-NMR (400 MHz, CDCl₃) δ 10.37 (s, 1H),8.66 (s, 1H), 8.15-8.05 (m, 1H), 7.45-7.35 (m, 1H), 7.30-7.15 (m, 3H),6.31 (d, J=8 Hz, 1H), 4.25-4.15 (m, 1H), 4.07 (q, J=7 Hz, 2H), 3.43-3.31(m, 2H), 3.25-3.15 (m, 2H), 2.25-2.10 (m, 2H), 2.10-1.70 (m, 4H), 1.57(s, 9H) 1.47 (t, J=7 Hz, 3H).

Example 76 (R)-tert-Butyl2-(2-fluorophenyl)-4-(1-cyclopropylmethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

Following the procedure for Example 506 starting with(R)—N-(1-(1-cyclopropylmethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylicacid gave (R)-tert-butyl2-(2-fluorophenyl)-4-(1-cyclopropylmethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateas a cream solid (350 mg, 70%). ¹H-NMR (400 MHz, CDCl₃) δ 10.36 (s, 1H),8.66 (s, 1H), 8.15-8.05 (m, 1H), 7.45-7.35 (m, 1H), 7.28-7.15 (m, 3H),6.31 (d, J=7.5 Hz, 1H), 4.25-4.15 (m, 1H), 3.95-3.85 (m, 2H), 3.43-3.30(m, 2H), 3.28-3.15 (m, 2H), 2.25-2.08 (m, 2H), 2.08-1.70 (m, 4H), 1.55(s, 9H), 1.35-1.20 (m, 1H), 0.70-0.60 (m, 2H), 0.50-0.35 (m, 2H).

Example 77 (R)-tert-Butyl2-(2-fluorophenyl)-4-(1-cyclopropyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

Following the procedure for Example 506 starting with(R)—N-(1-(1-cyclopropyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamideand 5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylicacid gave (R)-tert-butyl2-(2-fluorophenyl)-4-(1-cyclopropyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateas a cream solid (370 mg, 76%). ¹H-NMR (400 MHz, CDCl₃) δ 10.36 (s, 1H),8.69 (s, 1H), 8.12-8.00 (m, 1H), 7.45-7.30 (m, 1H), 7.28-7.15 (m, 3H),6.40-6.27 (m, 1H), 4.30-4.15 (m, 1H), 3.43-3.15 (m, 5H), 2.25-1.75 (m,6H), 1.55 (s, 9H), 1.35-1.15 (m, 2H), 1.10-0.95 (m, 2H).

Example 78 tert-Butyl(1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate

A solution of 5-chloro-1-methyl-4-nitro-1H-pyrazole (1.9 g, 11.77 mmol),4-(boc-aminomethyl)piperidine (3.78 g, 17.66 mmol) and DIPEA (6.15 mL,35.31 mmol) in EtOH (20 mL) was heated in a microwave at 130° C. for 1hr. The solvent was removed under reduced pressure and the residuere-dissolved in DCM. The organic layer was washed with water, passedthrough a phase separation cartridge and concentrated under reducedpressure. The residue was purified via silica gel column chromatography(0-100% EtOAc/isohexane) to yield tert-butyl(1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate as ayellow solid (3.95 g, 98%). To a solution of this solid (3.84 g, 11.30mmol) in MeOH (125 mL) was added 10% Pd/C (0.42 g, 3.96 mmol) andammonium formate (2.85 g, 45.2 mmol). The mixture was heated at 80° C.for 2.5 hr. The mixture was concentrated under reduced pressure and theresidue was re-dissolved in EtOAc and washed with water. The organiclayer was passed through a phase separation cartridge and concentratedunder reduced pressure to give tert-butyl(1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate as abrown oil (3.49 g, 99%). ¹H NMR (400 MHz, CDCl₃) δ 7.04 (s, 1H), 4.63(s, 1H), 3.64 (s, 3H), 3.11-3.07 (m, 6H), 2.67 (s, 2H), 1.77 (d, J=12.8Hz, 2H), 1.45 (s, 9H), 1.39-1.26 (m, 2H). 1H hidden by water peak.

Example 79 tert-Butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate

A solution of PyBOP (2.84 g, 5.46 mmol) and2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid (1.39 g,4.29 mmol) in DCM (10 mL) was stirred at room temperature for 30 min. Asolution of tert-butyl(1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate (1.2g, 3.90 mmol) and DIPEA (1.1 mL, 6.24 mmol) in DCM (20 mL) was added andthe mixture stirred at room temperature for 16 hr. The mixture wasdiluted with DCM and washed with water. The organic layer was separated,passed through a phase separation cartridge and concentrated underreduced pressure. The residue was purified via silica gel columnchromatography (0-100% EtOAc/isohexane) to yield tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateas a pink solid (2.32 g, 96%). ¹H NMR (400 MHz, d₆-DMSO) δ 10.62 (s,1H), 9.64 (s, 1H), 7.23 (s, 1H), 6.86 (t, J=5.8 Hz, 1H), 3.62 (s, 3H),3.07 (d, J=11.4 Hz, 2H), 2.95 (t, J=11.5 Hz, 2H), 2.87 (t, J=6.3 Hz,2H), 1.67 (d, J=12.3 Hz, 2H), 1.52 (s, 9H), 1.45 (s, 1H), 1.40 (s, 9H),1.27-1.16 (m, 2H).

Example 805-(tert-Butoxycarbonylamino)-2-(2,6-difluoro-3-methoxyphenyl)thiazole-4-carboxylicacid

Following the procedure for Examples 19-23 starting with2,6-difluoro-3-methoxybenzoyl chloride gave5-(tert-butoxycarbonylamino)-2-(2,6-difluoro-3-methoxyphenyl)thiazole-4-carboxylicacid as a pale yellow solid (120 mg, 70%). ¹H NMR (400 MHz, d₆-DMSO) δ7.32-7.23 (m, 1H), 7.22-7.15 (m, 1H), 3.88 (s, 3H), 1.49 (s, 9H).

Example 81 (R)-Benzyl1-(4-(5-tert-butoxycarbonyl-amino-2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate

A solution of PyBOP (1.31 g, 2.52 mmol) and2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid (0.61 g,1.89 mmol) in DCM (20 mL) was stirred at room temperature for 30 min. Asolution of (R)-benzyl azepan-4-ylcarbamate (0.62 g, 1.80 mmol) andDIPEA (0.5 mL, 2.88 mmol) in DCM (20 mL) was added and the mixturestirred at room temperature for 16 hr. The mixture was diluted with DCMand washed with water. The organic layer was separated, passed through aphase separation cartridge and concentrated under reduced pressure. Theresidue was purified via silica gel column chromatography (0-100%EtOAc/hexane) to yield (R)-benzyl1-(4-(5-tert-butoxycarbonyl-amino-2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamateas a pink solid (1.04 g, 89%). ¹H NMR (400 MHz, CDCl₃) δ 10.28 (s, 1H),8.40 (s, 1H), 7.75 (s, 1H), 7.38-7.27 (m, 5H), 5.09 (s, 2H), 5.00-4.92(m, 1H), 3.91-3.84 (m, 1H), 3.73 (s, 3H), 3.36-3.24 (m, 2H), 3.15-3.04(m, 2H), 2.19-2.03 (m, 2H), 1.96-1.79 (m, 3H), 1.75-1.63 (m, 1H), 1.52(s, 9H).

Example 82 (R)-tert-Butyl2-bromo-4-(1-methyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

Following the procedure for Example 528 starting with2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid and(R)—N-(azepan-4-yl)-2,2,2-trifluoroacetamide gave (R)-tert-butyl2-bromo-4-(1-methyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateas a salmon solid (500 mg, 74%). ¹H NMR (400 MHz, CDCl₃) δ 10.27 (s,1H), 8.38 (s, 1H), 7.74 (s, 1H), 6.41 (d, J=8.2 Hz, 1H), 4.23-4.15 (m,1H), 3.75 (s, 3H), 3.38-3.29 (m, 2H), 3.22-3.08 (m, 2H), 2.22-2.08 (m,2H), 2.03-1.93 (m, 2H), 1.88-1.69 (m, 2H), 1.52 (s, 9H).

Example 83 (R) 4-(benzyloxycarbonylamino)azepane or (5)4-(benzyloxycarbonylamino)azepane

To a 250 mL 3-neck-round bottom flask was added tert-butyl4-aminoazepane-1-carboxylate (8.80 g, 41.0 mmol), triethylamine (29 mL,0.21 mol) and methylene chloride (20 mL). The mixture was cooled to −20°C. and benzyl chloroformate (8.4 g, 49 mmol) was added dropwise via asyringe over 10 min. The heterogeneous mixture was warmed to roomtemperature and stirred for 2 h. The reaction was monitored by LCMS andupon completion of the reaction, the solvent was distilled off and thecrude product was purified via flash chromatography, heptane/ethylacetate 10% to 30% to afford a white solid (6.0 g, 42%).

The racemic azepine was resolved using chiral SFC with a Chiralpak OJ-H(100×4.6 mm, 5 micron) column, 15% Methanol/CO₂, with a flow rate of 200ml/min, pressure at 100 bars and at 40° C. for 5 min. to afford the twoenantiomers ((R)-tert-butyl4-(benzyloxycarbonylamino)azepane-1-carboxylate and (S)-tert-butyl4-(benzyloxycarbonylamino)azepane-1-carboxylate).

To a 100 mL round bottom flask was added one of the enantionmers,dioxane (20 mL) and 12N HCl (4 mL). The mixture was stirred for 2 h andthe solvent was distilled off. The product, an HCl salt, (2.2 g, 37%) ofisomer 1 and (2.4 g, 40%) of isomer 2 was used directly in the nextstep.

Table 1 Formula I Compounds 101-157 Example 1015-amino-2-(2,6-difluorophenyl)-N-(1H-pyrazol-4-yl)thiazole-4-carboxamide101

Following the procedures as described in Example 113,1H-pyrazol-4-amine,5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid and HATU were reacted to give 101 as a white solid (63 mg, 78%)over two steps. ¹H NMR (400 MHz, DMSO) δ 12.51 (s, 1H), 9.71 (s, 1H),7.95 (s, 1H), 7.74 (s, 1H), 7.65-7.44 (m, 1H), 7.27 (t, J=8.4, 2H).ESIMS m/z=322.0 (M+1)

Example 1025-amino-2-(2,6-difluorophenyl)-N-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide102

Following the procedures as described in Example 113,1-methyl-1H-pyrazol-4-amine,5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid and HATU were reacted to give 102 as a white solid (45 mg, 70%)over two steps. ¹H NMR (400 MHz, DMSO) δ 9.78 (s, 1H), 8.00 (d, J=37.3,1H), 7.70-7.47 (m, 4H), 7.28 (t, J=8.4, 2H), 3.81 (d, J=12.5, 3H). ESIMSm/z=336.1 (M+1)

Example 103(S)-5-amino-N-(5-(3-aminopiperidin-1-yl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide103

Following the procedures as described in Example 113, (S)-tert-butyl1-(4-amino-1H-pyrazol-5-yl)piperidin-3-ylcarbamate,5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid, and HATU were reacted to give 103 as a white solid (27 mg, 23%)over two steps. ¹H NMR (400 MHz, DMSO) δ 11.90 (s, 1H), 8.48 (s, 1H),7.86 (s, 1H), 7.54-7.49 (m, 2H), 7.28 (t, J=12 Hz, 2H), 3.19 (d, J=8 Hz,1H), 3.09 (d, J=8 Hz, 1H), 2.82-2.77 (m, 1H), 2.67-2.60 (m, 1H), 2.43(t, J=12 Hz, 1H), 1.84-1.81 (m, 1H), 1.75-1.55 (m, 2H), 1.15-1.08 (m,1H). ESIMS m/z=420.1 (M+1)

Example 1045-amino-2-(2-fluorophenyl)-N-(1-methyl-5-(piperidin-4-ylmethylamino)-1H-pyrazol-4-yl)thiazole-4-carboxamide104

Following the procedures as described in Example 113, tert-butyl4-((4-amino-1-methyl-1H-pyrazol-5-ylamino)methyl)piperidine-1-carboxylateand 5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylicacid, and HATU were reacted to give 104 as a white solid (5.4 mg, 10%)over two steps. ¹H NMR (400 MHz, DMSO) δ 9.06 (s, 1H), 8.32 (dd, J=15.5,6.0, 2H), 7.52-7.24 (m, 6H), 4.95 (t, J=6.7, 1H), 3.61 (s, 4H), 2.96 (t,J=22.0, 3H), 2.82 (t, J=6.5, 2H), 1.77 (d, J=12.5, 2H), 1.58 (s, 1H),1.25-1.04 (m, 2H). ESIMS m/z=430.1 (M+1)

Example 1055-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(piperidin-4-ylmethylamino)-1H-pyrazol-4-yl)thiazole-4-carboxamide105

Following the procedures as described in Example 113, tert-butyl4-((4-amino-1-methyl-1H-pyrazol-5-ylamino)methyl)piperidine-1-carboxylate,5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid and HATU were reacted to give 105 as a white solid (4.4 mg, 7.4%)over two steps. ¹H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 8.36 (s, 1H),7.67-7.36 (m, 3H), 7.27 (t, J=8.6, 2H), 4.88 (t, J=6.5, 1H), 3.63-3.55(m, 4H), 3.01 (d, J=12.2, 2H), 2.80 (t, J=6.5, 2H), 1.76 (d, J=11.1,2H), 1.55 (s, 1H), 1.24-1.01 (m, 2H). ESIMS m/z=448.1 (M+1)

Example 106(S)-5-amino-N-(5-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide106

Following the procedures as described in Example 113, (S)-tert-butyl1-(1-methyl-4-amino-1H-pyrazol-5-yl)piperidin-3-ylcarbamate,5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid, and HATU were reacted to give 106 as a white solid (32 mg, 11%)over two steps. ¹H NMR (400 MHz, DMSO) δ 8.80 (s, 1H), 7.60-7.42 (m,4H), 7.27 (t, J=8.7, 2H), 3.62 (d, J=10.3, 3H), 3.09 (dd, J=11.1, 3.3,1H), 3.03-2.88 (m, 2H), 2.83 (t, J=8.7, 1H), 2.69 (dd, J=11.0, 8.5, 1H),1.87-1.64 (m, 2H), 1.55 (d, J=8.9, 1H), 1.17 (dd, J=19.9, 9.3, 1H).ESIMS m/z=434.1 (M+1)

Example 107(S)-5-amino-N-(5-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide107

Following the procedures as described in Example 113, (S)-tert-butyl1-(1-methyl-4-amino-1H-pyrazol-5-yl)piperidin-3-ylcarbamate,5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylicacid, and HATU were reacted to give 107 as a white solid (36 mg, 13%)over two steps. ¹H NMR (400 MHz, DMSO) δ 9.02 (s, 1H), 8.29 (dd, J=8.6,7.0, 1H), 7.51-7.25 (m, 6H), 3.62 (d, J=13.9, 3H), 3.19-3.06 (m, 1H),2.96 (dt, J=18.1, 10.4, 2H), 2.81 (d, J=9.0, 1H), 2.69 (dd, J=16.1, 7.5,1H), 1.75 (dd, J=24.8, 8.7, 2H), 1.63-1.45 (m, 1H), 1.14 (dd, J=19.8,9.2, 1H). ESIMS m/z=416.1 (M+1)

Example 1085-amino-N-(5-(4-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide108

Following the procedures as described in Example 113, tert-butyl1-(1-methyl-4-amino-1H-pyrazol-5-yl)piperidin-4-ylcarbamate,5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid, and HATU were reacted to give 108 as a white solid (27 mg, 21%)over two steps. ¹H NMR (400 MHz, DMSO) δ 8.70 (s, 1H), 7.60-7.37 (m,4H), 7.27 (t, J=8.7, 2H), 3.62 (s, 3H), 3.12-2.92 (m, 4H), 2.66 (dd,J=11.9, 8.2, 1H), 1.77 (d, J=9.5, 2H), 1.36 (td, J=15.3, 4.7, 2H). ESIMSm/z=434.1 (M+1).

Example 1093-amino-N-(5-(4-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-phenylpicolinamide109

Following the procedures for Example 141, tert-butyl1-(1-methyl-4-amino-1H-pyrazol-5-yl)piperidin-4-ylcarbamate,3-amino-6-bromopicolinic acid and phenylboronic acid were converted to109 as a white solid (9.2 mg, 10%) over three steps. ¹H NMR (400 MHz,DMSO) δ 9.85 (s, 1H), 8.27 (s, 1H), 8.09 (d, J=7.3, 2H), 7.93 (d, J=8.8,1H), 7.61 (s, 1H), 7.53-7.27 (m, 4H), 6.99 (s, 2H), 3.66 (d, J=6.5, 3H),3.14 (dd, J=21.0, 9.8, 3H), 2.92 (s, 2H), 1.90 (d, J=10.4, 2H),1.68-1.40 (m, 2H). ESIMS m/z=392.1 (M+1)

Example 1103-amino-N-(5-(4-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide110

Following the procedures for Example 141, tert-butyl1-(1-methyl-4-amino-1H-pyrazol-5-yl)piperidin-4-ylcarbamate and3-amino-6-bromopicolinic acid were converted to 110 as a white solid (12mg, 11%) over three steps. ¹H NMR (400 MHz, DMSO) δ 9.81 (s, 1H), 8.06(td, J=8.1, 1.9, 1H), 7.74 (dd, J=8.7, 2.2, 1H), 7.65 (s, 1H), 7.51-7.21(m, 5H), 7.06 (s, 2H), 3.65 (d, J=7.3, 3H), 3.16-2.99 (m, 3H), 2.80-2.59(m, 2H), 1.79 (d, J=9.9, 2H), 1.52-1.16 (m, 2H). ESIMS m/z=410.1 (M+1)

Example 111(S)-3-amino-N-(5-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide111

Following the procedures for Example 141, (S)-tert-butyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-3-ylcarbamate and3-amino-6-bromopicolinic acid were converted to 111 as a white solid (29mg, 20%) over three steps. ¹H NMR (400 MHz, DMSO) δ 9.80 (d, J=17.7,1H), 8.06 (td, J=8.3, 1.9, 1H), 7.74 (dd, J=8.7, 2.2, 1H), 7.64 (d,J=12.2, 1H), 7.48-7.38 (m, 1H), 7.30 (ddd, J=8.1, 7.3, 3.7, 3H), 7.07(s, 2H), 3.67 (s, 3H), 3.11 (dd, J=10.7, 3.4, 1H), 3.07-2.88 (m, 2H),2.88-2.74 (m, 1H), 2.74 (s, 1H), 1.77 (ddd, J=33.8, 9.1, 4.0, 2H), 1.57(dd, J=21.5, 11.7, 1H), 1.22-1.06 (m, 1H). ESIMS m/z=410.1 (M+1)

Example 112(R)-3-amino-N-(5-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide112

Following the procedures for Example 141, (R)-tert-butyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-3-ylcarbamate and3-amino-6-bromopicolinic acid were converted to 112 as a white solid (26mg, 18%) over three steps. ¹H NMR (400 MHz, DMSO) δ 9.80 (d, J=17.5,1H), 8.06 (td, J=8.3, 1.8, 1H), 7.74 (dd, J=8.7, 2.2, 1H), 7.69-7.60 (m,1H), 7.50-7.37 (m, 1H), 7.37-7.20 (m, 3H), 7.07 (s, 2H), 3.67 (s, 3H),3.12 (dd, J=10.8, 3.4, 1H), 2.98 (qd, J=11.3, 5.0, 2H), 2.90-2.76 (m,1H), 2.76-2.63 (m, 1H), 1.93-1.66 (m, 2H), 1.57 (dd, J=21.7, 12.5, 1H),1.12 (td, J=13.0, 3.6, 1H). ESIMS m/z=410.1 (M+1)

Example 1135-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide113

To a 100 mL round bottom flask containing tert-butyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate (410 mg, 1.32mmol),5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid (496 mg, 1.40 mmol) and HATU (1.51 g, 4.00 mmol) was addedmethylene chloride (20 mL) and diisopropylethylamine (1.30 g, 10.0mmol). The reaction mixture was stirred for 24 hr at room temperatureand the reaction was monitored by LCMS. Upon completion of the reaction,the solvent was distilled off and the crude material was purified viaflash chromatography, heptane/ethyl acetate 20% to 95% to afford yellowoil (598 mg, 71%). In a 50 mL round bottom flask was added the amide(598 mg, 0.923 mmol), dioxane (10 mL) and hydrochloric acid (1 mL, 32.4mmol). The mixture was stirred at 60° C. for 2 h, and the solvent wasdistilled off. The crude product was purified via reverse phase HPLC 40%to 80% MeOH in water with 0.1% NH₄OH to afford 113 as a white solid (90mg, 22%). ¹H NMR (400 MHz, DMSO)¹H NMR (400 MHz, DMSO) δ 8.75 (s, 1H),8.46 (s, 1H), 7.61-7.43 (m, 3H), 7.27 (t, J=8.8, 2H), 3.65 (s, 3H),3.19-3.04 (m, 6H), 1.99-1.70 (m, 2H), 1.59 (dd, J=14.1, 9.0, 3H).; ESIMSm/z=448.1 (M+1)

Example 1143-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide114

Following the procedures as described in Example 141, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example16, 3-amino-6-bromopicolinic acid, and 2-fluorophenylboronic acid wereconverted to 114 as a white solid (21 mg, 26%) over three steps. ¹H NMR(400 MHz, DMSO) δ 9.72 (s, 1H), 8.05 (dd, J=11.3, 4.9, 1H), 7.75 (dd,J=8.8, 2.1, 1H), 7.32 (td, J=7.6, 3.7, 3H), 7.07 (s, 2H), 3.69 (s, 3H),3.27-3.07 (m, 4H), 2.13-1.51 (m, 7H). ESIMS m/z=424.1 (M+1)

Example 1155-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(piperidin-4-ylmethoxy)-1H-pyrazol-4-yl)thiazole-4-carboxamide115

Following the procedures as described in Example 113, (S)-tert-butyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-ylcarbamate,5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid, and HATU were reacted to give 115 as a white solid (11 mg, 11%)over two steps. ¹H NMR (400 MHz, DMSO) δ 8.69 (s, 1H), 8.34 (s, 1H),7.70-7.40 (m, 3H), 7.38 (s, 1H), 7.26 (t, J=8.6, 1H), 3.99 (d, J=6.1,2H), 3.68-3.54 (m, 3H), 3.04 (d, J=12.5, 3H), 2.70-2.53 (m, 2H),1.99-1.66 (m, 2H), 1.27 (dd, J=21.3, 12.3, 2H). ESIMS m/z=449.1 (M+1)

Example 1163-amino-6-(2-fluorophenyl)-N-(1-methyl-5-(piperidin-4-yloxy)-1H-pyrazol-4-yl)picolinamide116

Following the procedures for Example 141, tert-butyl4-(4-amino-1-methyl-1H-pyrazol-5-yloxy)piperidine-1-carboxylate and3-amino-6-bromopicolinic acid were coupled and the intermediate amidewas reacted with 2-fluorophenylboronic acid under palladium catalyzedSuzuki conditions to give 116 as a white solid (10 mg, 14%) over threesteps. ¹H NMR (400 MHz, DMSO) δ 9.67 (s, 1H), 8.05 (t, J=7.5, 1H), 7.73(dd, J=8.8, 1.9, 1H), 7.66-7.38 (m, 3H), 7.38-7.25 (m, 3H), 7.03 (s,2H), 4.43-4.20 (m, 1H), 3.63 (s, 3H), 2.96-2.79 (m, 2H), 2.39 (dd,J=26.9, 16.6, 2H), 1.92 (d, J=12.0, 2H), 1.55 (td, J=13.2, 3.9, 2H).ESIMS m/z=411.1 (M+1)

Example 1173-amino-6-(2-fluorophenyl)-N-(1-methyl-5-(piperidin-4-ylmethoxy)-1H-pyrazol-4-yl)picolinamide117

Following the procedures for Example 141, tert-butyl4-((4-amino-1-methyl-1H-pyrazol-5-yloxy)methyl)piperidine-1-carboxylateand 3-amino-6-bromopicolinic acid were reacted to give3-amino-6-bromo-N-(1-methyl-5-(piperidin-4-ylmethoxy)-1H-pyrazol-4-yl)picolinamide,which was reacted with 2-fluorophenylboronic acid under palladiumcatalyzed Suzuki conditions to give 117 as a white solid (6.7 mg, 7.2%)over three steps. ¹H NMR (400 MHz, DMSO) δ 9.66 (s, 1H), 8.10 (t, J=7.2,1H), 7.71 (dt, J=37.9, 19.0, 1H), 7.60-7.25 (m, 5H), 7.03 (s, 2H), 3.97(d, J=6.2, 2H), 3.72-3.42 (m, 3H), 2.76 (t, J=31.9, 2H), 2.36 (t,J=12.2, 2H), 1.88-1.53 (m, 3H), 1.25-0.99 (m, 2H). ESIMS m/z=425.1 (M+1)

Example 1183-amino-N-(5-(4-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-bromopyrazine-2-carboxamide118

Following the procedures for Example 141, tert-butyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-4-amine was converted to118 as a white solid (0.83 mg, 0.5%) over two steps. ESIMS m/z=396.1(M+1)

Example 119(S)-3-amino-N-(5-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide119

To a 50 mL round bottom flask containing (S)-tert-butyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-3-ylcarbamate (100 mg,0.34 mmol), 3-amino-6-bromopyrazine-2-carboxylic acid (111 mg, 0.51mmol) and HATU (0.39 g, 1.02 mmol) was added methylene chloride (10 mL)and diisopropylethylamine (0.18 g, 1.35 mmol). The reaction mixture wasstirred for 24 hr at room temperature and the reaction was monitored byLCMS. Upon completion of the reaction, the solvent was distilled off andthe crude material was purified via flash chromatography, heptane/ethylacetate 20% to 95% to afford the coupled product amide as a white solid(153 mg, 91%).

To a 10 mL microwave vial was added the amide (153 mg, 0.31 mmol),2-fluorophenylboronic acid (130 mg, 0.93 mmol),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (50 mg,0.062 mmol), a 2M solution of Na₂CO₃ (1 mL) and 1,2-dimethoxyethane (3mL). The mixture was irradiated to 130° C. with a microwave for 30 minand the mixture was cooled, concentrated and purified via flashchromatography, heptane/ethyl acetate 20% to 95% to afford theBoc-aminopiperidine intermediate as a brown oil.

To a 50 mL round bottom flask was added the Boc-aminopiperidineintermediate, dioxane (4 mL) and hydrochloric acid (0.5 mL, 16 mmol).The mixture was stirred at 60° C. for 2 h, and the solvent was distilledoff. The crude product was purified via reverse phase HPLC 40% to 80%MeOH in water with 0.1% NH₄OH to afford 119 as obtained as a white solid(9.0 mg, 9.5%) over two steps. ¹H NMR (400 MHz, DMSO) δ 8.69 (d, J=2.3,1H), 8.16 (t, J=7.9, 1H), 7.74 (s, 2H), 7.58-7.41 (m, 2H), 7.35 (dd,J=13.7, 5.5, 2H), 3.66 (s, 3H), 3.13 (d, J=7.7, 2H), 3.05-2.76 (m, 4H),2.70 (dd, J=18.8, 10.2, 1H), 1.89-1.65 (m, 2H), 1.56 (d, J=10.4, 1H),1.24-1.05 (m, 1H). ESIMS m/z=411.1 (M+1)

Example 1205-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(piperidin-4-yloxy)-1H-pyrazol-4-yl)thiazole-4-carboxamide120

Following the procedures as described in Example 113, tert-butyl4-(4-amino-1-methyl-1H-pyrazol-5-yloxy)piperidine-1-carboxylate,5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid, and HATU were reacted to give 120 as a white solid (20 mg, 9.0%)over two steps. ¹H NMR (400 MHz, DMSO) δ 8.62 (s, 1H), 7.64-7.40 (m,3H), 7.27 (t, J=8.7, 2H), 4.39-4.11 (m, 1H), 3.60 (s, 3H), 2.94 (dt,J=12.5, 3.9, 2H), 2.50-2.40 (m, 2H), 2.03-1.81 (m, 2H), 1.53 (td,J=13.2, 4.0, 2H). ESIMS m/z=435.1 (M+1).

Example 121(S)-3-amino-N-(5-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-bromopyrazine-2-carboxamide121

Following the procedures for Example 141, (S)-tert-butyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-3-ylcarbamate wasconverted to 121 as a white solid (153 mg, 91%) over two steps. ESIMSm/z=396.1 (M+1)

Example 1223-amino-N-(5-(4-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide122

Following the procedures for Example 141, Boc-protected1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-4-amine, the titlecompound was converted to 122 as a white solid (9.0 mg, 9.5%) over threesteps. ¹H NMR (400 MHz, DMSO) δ 8.69 (d, J=2.3, 1H), 8.16 (t, J=7.9,1H), 7.74 (s, 2H), 7.58-7.41 (m, 2H), 7.35 (dd, J=13.7, 5.5, 2H), 3.66(s, 3H), 3.13 (d, J=7.7, 2H), 3.05-2.76 (m, 4H), 2.70 (dd, J=18.8, 10.2,1H), 1.89-1.65 (m, 2H), 1.56 (d, J=10.4, 1H), 1.24-1.05 (m, 1H). ESIMSm/z=411.1 (M+1)

Example 123(S)-3-amino-N-(5-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-chloropyrazine-2-carboxamide123

Following the procedures for Example 141, (S)-tert-butyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-3-ylcarbamate wasconverted to 123 as a white solid (4.4 mg, 40%) over two steps. ESIMSm/z=351.1 (M+1)

Example 124(R)-3-amino-N-(5-(3-aminopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide124

Following the procedures for Example 141, (R)-tert-butyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-ylcarbamate and3-amino-6-bromopicolinic acid were converted to 124 as a white solid (36mg, 32%) over three steps. ¹H NMR (400 MHz, DMSO) δ 7.96 (td, J=8.3,1.7, 1H), 7.81-7.66 (m, 2H), 7.53-7.23 (m, 4H), 7.03 (s, 2H), 3.65 (s,3H), 3.44 (m, 3H), 2.81 (dt, J=69.2, 34.6, 1H), 1.96 (tt, J=21.1, 10.6,2H), 1.65 (ddd, J=16.0, 7.6, 4.0, 1H). ESIMS m/z=396.1 (M+1)

Example 125(S)-3-amino-N-(5-(3-aminopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide125

Following the procedures for Example 141, (S)-tert-butyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-ylcarbamate and3-amino-6-bromopicolinic acid were converted to 125 as a white solid (50mg, 44%) over three steps. ¹H NMR (400 MHz, DMSO) δ 7.96 (td, J=8.3,1.8, 1H), 7.81-7.59 (m, 2H), 7.55-7.12 (m, 4H), 7.03 (s, 2H), 3.65 (s,3H), 3.44 (m, 4H), 2.85 (dd, J=9.4, 2.8, 1H), 1.96 (tt, J=21.1, 10.6,1H), 1.77-1.49 (m, 1H). ESIMS m/z=396.1 (M+1)

Example 126(R)-5-amino-N-(5-(3-aminopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide126

Following the procedures as described in Example 113, (R)-tert-butyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-ylcarbamate,5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid, and HATU were reacted to give 126 as a white solid (38 mg, 32%)over two steps. ¹H NMR (400 MHz, DMSO) δ 7.67 (d, J=19.5, 1H), 7.62-7.45(m, 3H), 7.28 (t, J=8.7, 2H), 3.63 (s, 3H), 3.53 (s, 1H), 3.20 (dt,J=8.9, 4.4, 2H), 2.84 (d, J=10.2, 2H), 2.05-1.84 (m, 2H), 1.75 (s, 2H).ESIMS m/z=420.1 (M+1)

Example 127(S)-5-amino-N-(5-(3-aminopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide127

Following the procedures as described in Example 113, (S)-tert-butyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-ylcarbamate,5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid, and HATU were reacted to give 127 as a white solid (20 mg, 17%)over two steps. ¹H NMR (400 MHz, DMSO) δ 7.67 (d, J=19.5, 1H), 7.62-7.45(m, 3H), 7.28 (t, J=8.7, 2H), 3.63 (s, 3H), 3.53 (s, 1H), 3.20 (dt,J=8.9, 4.4, 2H), 2.84 (d, J=10.2, 2H), 2.05-1.84 (m, 2H), 1.75 (s, 2H).ESIMS m/z=420.1 (M+1)

Example 128(S)-3-amino-N-(5-(3-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide128

Following the procedures for Example 141, (R)-tert-butyl(1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-3-yl)methylcarbamate,3-amino-6-bromopicolinic acid were coupled and the intermediate amidewas reacted with 2-fluorophenylboronic acid under palladium catalyzedSuzuki conditions to give 128 as a white solid (27 mg, 15%) over threesteps. ¹H NMR (400 MHz, DMSO) δ 9.82 (s, 1H), 8.04 (t, J=8.0, 1H),7.81-7.60 (m, 2H), 7.38 (ddd, J=22.0, 13.3, 7.2, 5H), 7.07 (s, 4H), 3.68(s, 3H), 3.15-2.94 (m, 3H), 2.75 (dt, J=17.3, 10.2, 3H), 2.01-1.47 (m,4H), 1.25-1.01 (m, 1H). ESIMS m/z=424.1 (M+1)

Example 129(R)-3-amino-N-(5-(3-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide129

Following the procedures for Example 141, (R)-tert-butyl(1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-3-yl)methylcarbamate,3-amino-6-bromopicolinic acid were coupled and the intermediate amidewas reacted with 2-fluorophenylboronic acid under palladium catalyzedSuzuki conditions to give 129 as a white solid (33 mg, 18%) over threesteps. ¹H NMR (400 MHz, DMSO) δ 9.82 (s, 1H), 8.03 (dt, J=9.6, 4.8, 1H),7.81-7.60 (m, 2H), 7.49-7.20 (m, 4H), 7.07 (s, 2H), 3.67 (s, 3H),3.30-3.20 (m, 2H), 3.15-2.96 (m, 3H), 2.73 (dd, J=25.7, 14.9, 1H),1.92-1.44 (m, 4H), 1.03 (dd, J=21.1, 10.1, 1H). ESIMS m/z=424.1 (M+1)

Example 1303-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide130

Following the procedures for Example 141, tert-butyl(1-(4-amino-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate,3-amino-6-bromopicolinic acid were coupled and the intermediate amidewas reacted with 2-fluorophenylboronic acid under palladium catalyzedSuzuki conditions to give 130 as a white solid (29 mg, 16%) over threesteps. ¹H NMR (400 MHz, DMSO) δ 9.83 (d, J=16.2, 1H), 8.47 (s, OH), 8.04(dd, J=15.8, 8.0, 1H), 7.69 (dd, J=37.1, 16.6, 2H), 7.51-7.27 (m, 5H),7.09 (s, 2H), 3.66 (s, 3H), 3.06 (dd, J=21.6, 10.3, 6H), 1.74 (t,J=17.5, 2H), 1.28 (dd, J=39.1, 27.5, 3H). ESIMS m/z=424.1 (M+1)

Example 131(S)-5-amino-N-(5-(3-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide131

Following the procedures as described in Example 113, (R)-tert-butyl(1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-3-yl)methylcarbamate,5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid, and HATU were reacted to give 131 as a white solid (12 mg, 6.2%)over two steps. ¹H NMR (400 MHz, DMSO) δ 8.74 (d, J=4.0, 1H), 7.60-7.42(m, 4H), 7.28 (t, J=8.8, 2H), 3.63 (d, J=3.3, 3H), 3.24-2.81 (m, 4H),2.77-2.61 (m, 2H), 1.84-1.42 (m, 4H), 1.03 (d, J=10.6, 1H). ESIMSm/z=448.1 (M+1)

Example 132R-5-amino-N-(5-(3-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide132

Following the procedures as described in Example 113, (S)-tert-butyl(1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-3-yl)methylcarbamate,5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid, and HATU were reacted to give 132 as a white solid (9.6 mg, 5.0%)over two steps. ¹H NMR (400 MHz, DMSO) δ 8.74 (d, J=4.0, 1H), 7.60-7.42(m, 4H), 7.28 (t, J=8.8, 2H), 3.63 (d, J=3.3, 3H), 3.24-2.80 (m, 4H),2.77-2.61 (m, 2H), 1.82-1.42 (m, 4H), 1.03 (d, J=10.6, 1H). ESIMSm/z=448.1 (M+1)

Example 1335-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide133

Following the procedures as described in Example 113, tert-butyl(1-(4-amino-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate,5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid, and HATU were reacted to give 133 as a white solid (40 mg, 21%)over two steps. ¹H NMR (400 MHz, DMSO) δ 8.76 (d, J=6.8, 1H), 7.62-7.38(m, 4H), 7.38-7.16 (m, 2H), 3.63 (s, 3H), 3.15-2.94 (m, 5H), 2.88 (t,J=6.4, 1H), 1.86-1.60 (m, 2H), 1.42-1.05 (m, 3H). ESIMS m/z=448.1 (M+1)

Example 134(S)-3-amino-N-(5-(3-(aminomethyl)pyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide134

Following the procedures for Example 141, (S)-tert-butyl(1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-yl)methylcarbamate and3-amino-6-bromopicolinic acid were coupled and the intermediate amidewas reacted with 2-fluorophenylboronic acid under palladium catalyzedSuzuki conditions to give 134 as a white solid (76 mg, 48%) over threesteps. ¹H NMR (400 MHz, DMSO) δ 9.75 (s, 1H), 8.05 (t, J=7.9, 1H), 7.73(dd, J=8.7, 2.0, 1H), 7.57 (s, 1H), 7.49-7.22 (m, 4H), 7.07 (s, 2H),3.65 (s, 3H), 3.33-3.18 (m, 4H), 3.00 (dd, J=8.8, 6.3, 2H), 2.23 (dt,J=13.9, 7.0, 1H), 1.97 (td, J=12.5, 7.1, 1H), 1.68-1.55 (m, 1H). ESIMSm/z=410.1 (M+1)

Example 135R-5-amino-N-(5-(3-(aminomethyl)pyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide135

Following the procedures as described in Example 113, (R)-tert-butyl(1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-yl)methylcarbamate,5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid, and HATU were reacted to give 135 as a white solid (39 mg, 27%)over two steps. ¹H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 7.61-7.45 (m,3H), 7.41 (d, J=5.1, 1H), 7.28 (t, J=8.6, 2H), 3.62 (s, 3H), 3.30-3.20(m, 4H), 2.97 (dt, J=19.0, 9.5, 1H), 2.61 (d, J=6.9, 1H), 2.34-2.18 (m,1H), 1.96 (tt, J=29.5, 14.8, 1H), 1.58 (dq, J=14.3, 7.2, 1H). ESIMSm/z=434.1 (M+1)

Example 136(R)-3-amino-N-(5-(3-(aminomethyl)pyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide136

Following the procedures for Example 141, (R)-tert-butyl(1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-yl)methylcarbamate and3-amino-6-bromopicolinic acid were coupled and the intermediate amidewas reacted with 2-fluorophenylboronic acid under palladium catalyzedSuzuki conditions to give 136 as a white solid (51 mg, 37%) over threesteps. ¹H NMR (400 MHz, DMSO) δ 9.75 (s, 1H), 8.04 (dd, J=11.3, 4.6,1H), 7.73 (dd, J=8.7, 2.0, 1H), 7.57 (s, 1H), 7.51-7.23 (m, 4H), 7.07(s, 2H), 3.65 (s, 3H), 3.30-3.20 (m, 3H), 3.00 (dd, J=8.8, 6.3, 2H),2.35-2.12 (m, 2H), 1.97 (td, J=12.4, 7.2, 1H), 1.56 (tt, J=40.8, 20.4,1H). ESIMS m/z=410.1 (M+1)

Example 137(S)-5-amino-N-(5-(3-(aminomethyl)pyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide137

Following the procedures as described in Example 113, (S)-tert-butyl(1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-yl)methylcarbamate,5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid, and HATU were reacted to give 137 as a white solid (56 mg, 33%)over two steps. ¹H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 7.61-7.45 (m,3H), 7.41 (d, J=5.1, 1H), 7.28 (t, J=8.6, 2H), 3.62 (s, 3H), 3.31-3.20(m, 4H), 2.98 (dt, J=19.0, 9.5, 1H), 2.61 (d, J=6.9, 1H), 2.34-2.19 (m,1H), 1.96 (tt, J=29.5, 14.8, 1H), 1.60 (dq, J=14.3, 7.2, 1H). ESIMSm/z=434.1 (M+1)

Example 1385-amino-2-(2,6-difluorophenyl)-N-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide138

Following the procedures as described in Example 113,1-(oxetan-3-yl)-1H-pyrazol-4-amine,5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid, and HATU were reacted to give 138 as a white solid (10 mg, 9%)over two steps. ¹H NMR (400 MHz, DMSO) δ 9.93 (s, 1H), 8.36 (s, 1H),7.86 (s, OH), 7.67-7.41 (m, 1H), 7.28 (t, J=8.4, 1H), 5.46-5.26 (m, 2H),4.90 (s, 1H), 4.40 (d, J=5.7, 2H). ESIMS m/z=378.0 (M+1)

Example 139(S)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide139

Following the procedures as described in Example 140, (S)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate,5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid, and HATU were reacted to give 139 as a white solid (42 mg, 25%)over two steps. ¹H NMR (400 MHz, DMSO) δ 8.81 (s, 1H), 7.62-7.44 (m,4H), 7.28 (t, J=8.7, 2H), 3.66 (d, J=17.1, 3H), 3.21-2.93 (m, 5H),1.93-1.73 (m, 3H), 1.69-1.40 (m, 3H). ESIMS m/z=448.1 (M+1)

Example 140R-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide140

To a 100 mL round bottom flask containing (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16(154 mg, 0.45 mmol),5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid (168 mg, 0.47 mmol) and HATU (0.51 g, 1.30 mmol) was addedmethylene chloride (10 mL) and diisopropylethylamine (0.44 g, 3.40mmol). The reaction mixture was stirred for 24 hr at room temperatureand the reaction was monitored by LCMS. Upon completion of the reaction,the solvent was distilled off and the crude material was purified viaflash chromatography, heptane/ethyl acetate 20% to 95% to afford yellowoil (270 mg, 88%).

In a 50 mL round bottom flask was added the amide (270 mg, 0.40 mmol),methylene chloride (8 mL) and a 1M solution of boron tribromide inCH₂Cl₂ (1 mL, 1.19 mmol). The mixture was stirred for 5 h, and thesolvent was distilled off. The crude product was purified via reversephase HPLC 40% to 80% MeOH in water with 0.1% NH₄OH to afford 140 as awhite solid (50 mg, 33%). ¹H NMR (400 MHz, DMSO) δ 8.81 (s, 1H),7.62-7.44 (m, 4H), 7.28 (t, J=8.7, 2H), 3.66 (d, J=17.1, 3H), 3.21-2.93(m, 5H), 1.93-1.73 (m, 3H), 1.69-1.40 (m, 3H). ESIMS m/z=448.1 (M+1)

Example 141(R)-3-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide141

To a 50 mL round bottom flask containing (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16(60 mg, 0.17 mmol), 3-amino-6-bromopyrazine-2-carboxylic acid (42 mg,0.19 mmol) and HATU (0.27 g, 1.30 mmol) was added methylene chloride (10mL) and diisopropylethylamine (0.18 g, 1.4 mmol). The reaction mixturewas stirred for 24 hr at room temperature and the reaction was monitoredby LCMS. Upon completion of the reaction, the solvent was distilled offand the crude material was purified via flash chromatography,heptane/ethyl acetate 20% to 95% to afford a white solid (75 mg, 79%).

To a 10 mL microwave vial was added the amide (75 mg, 0.14 mmol),2-fluorophenylboronic acid (59 mg, 0.42 mmol),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (23 mg,0.028 mmol), a 2M solution of Na₂CO₃ (1 mL) and 1,2-dimethoxyethane (3mL). The mixture was irradiated to 130° C. with a microwave for 30 minand the mixture was cooled, concentrated and purified via flashchromatography, heptane/ethyl acetate 20% to 95% to afford a brown oil.

To a 50 mL round bottom flask was added the pyrazine bromide, methylenechloride (4 mL) and a 1M solution of boron tribromide in CH₂Cl₂ (0.92mL, 0.9 mmol). The mixture was stirred for 5 h, and the solvent wasdistilled off. The crude product was purified via reverse phase HPLC 40%to 80% MeOH in water with 0.1% NH₄OH to afford 141 (23 mg, 39%) as awhite solid over two steps. ¹H NMR (400 MHz, DMSO) δ 8.68 (d, J=2.4,1H), 8.11 (td, J=8.1, 1.8, 1H), 7.76 (s, 2H), 7.57 (d, J=8.1, 1H), 7.47(dd, J=13.3, 5.7, 1H), 7.42-7.28 (m, 2H), 3.67 (s, 3H), 3.26-2.95 (m,5H), 1.96-1.73 (m, 3H), 1.54 (ddd, J=14.4, 12.4, 4.9, 3H). ESIMSm/z=425.1 (M+1)

Example 142(S)-3-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide142

Following the procedures for Example 141, (S)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate and3-amino-6-bromopicolinic acid were converted to 142 as a white solid (54mg, 69%) over three steps. ¹H NMR (400 MHz, DMSO) δ 9.73 (s, 1H), 8.05(t, J=7.3, 1H), 7.74 (dd, J=8.7, 2.1, 1H), 7.60 (s, 1H), 7.50-6.80 (m,2H), 6.58 (s, 3H), 3.69 (s, 3H), 3.27-3.13 (m, 4H), 1.85 (ddd, J=42.7,41.6, 18.5, 7H). ESIMS m/z=424.1 (M+1)

Example 143(S)-3-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide143

Following the procedures of Example 141, (S)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate was convertedto 143 as a white solid (13 mg, 22%) over three steps. ¹H NMR (400 MHz,DMSO) δ 8.68 (d, J=2.4, 1H), 8.11 (td, J=8.1, 1.8, 1H), 7.76 (s, 2H),7.57 (d, J=8.1, 1H), 7.47 (dd, J=13.3, 5.7, 1H), 7.42-7.28 (m, 2H), 3.67(s, 3H), 3.26-2.95 (m, 5H), 1.96-1.73 (m, 3H), 1.54 (ddd, J=14.4, 12.4,4.9, 3H). ESIMS m/z=425.1 (M+1)

Example 144R-5-amino-N-(5-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide144

Following the procedures as described in Example 113, (R)-tert-butyl1-(1-methyl-4-amino-1H-pyrazol-5-yl)piperidin-3-ylcarbamate,5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid, and HATU were reacted to give 144 as a white solid (32 mg, 11%)over two steps. ¹H NMR (400 MHz, DMSO) δ 8.81 (s, 1H), 7.63-7.42 (m,4H), 7.27 (t, J=8.7, 2H), 3.62 (d, J=10.3, 3H), 3.07 (dd, J=11.1, 3.3,1H), 3.03-2.80 (m, 2H), 2.83 (t, J=8.7, 1H), 2.69 (dd, J=11.0, 8.5, 1H),1.87-1.64 (m, 2H), 1.55 (d, J=8.9, 1H), 1.17 (dd, J=19.9, 9.3, 1H).ESIMS m/z=434.1 (M+1)

Example 145(R)-3-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide145

Following the procedures for Example 141, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16and 3-amino-6-bromopicolinic acid were converted to 145 as a white solid(21 mg, 26%) over three steps. ¹H NMR (400 MHz, DMSO) δ 9.72 (s, 1H),8.05 (dd, J=11.3, 4.9, 1H), 7.75 (dd, J=8.8, 2.1, 1H), 7.32 (td, J=7.6,3.7, 3H), 7.07 (s, 2H), 3.69 (s, 3H), 3.27-3.07 (m, 4H), 2.13-1.51 (m,7H). ESIMS m/z=424.1 (M+1)

Example 146(R)—N-(5-(3-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide146

Following the procedures as described in Example 113 and starting with(R)-tert-butyl(1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-3-yl)methylcarbamate and2-(2,6-difluorophenyl)thiazole-4-carboxylic acid were converted to 146as a white solid (9.7 mg, 5.0%) over two steps. ¹H NMR (400 MHz, DMSO) δ9.45 (s, 1H), 8.65 (s, 1H), 8.30 (s, 1H), 7.75-7.62 (m, 1H), 7.39 (dd,J=19.2, 10.4, 3H), 3.64 (d, J=7.7, 3H), 3.22 (d, J=11.6, 3H), 3.11-2.92(m, 3H), 2.82-2.64 (m, 3H), 1.76 (dd, J=38.1, 20.2, 3H), 1.55 (d,J=10.0, 1H), 1.11 (d, J=10.5, 1H). ESIMS m/z=433.1 (M+1)

Example 147 (R)-benzyl1-(4-(5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate147

Following the procedures as described in Example 140 and starting with(S)-benzyl 1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate,5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid, and HATU were converted to 147 as a white solid (26 mg, 32%) overtwo steps. ¹H NMR (400 MHz, DMSO) δ 8.67 (s, 1H), 7.59-7.42 (m, 4H),7.29 (dt, J=17.1, 7.3, 7H), 4.99 (s, 2H), 3.65 (s, 4H), 3.28-3.05 (m,4H), 2.05-1.75 (m, 3H), 1.68 (dd, J=20.2, 10.3, 3H). ESIMS m/z=582.1(M+1)

Example 148(R)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide148

Following the procedures as described in Example 140, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example16, 2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU wereconverted to 148 as a white solid (3.6 mg, 2.6%) over two steps. ESIMSm/z=433.1 (M+1)

Example 149(S)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide149

Following the procedures as described in Example 140, (S)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate,2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU wereconverted to 149 as a white solid (2.1 mg, 1.5%) over two steps. ESIMSm/z=433.1 (M+1)

Example 1505-amino-N-(5-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide150

Following the procedures as described in Example 113, tert-butyl3-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-ylcarbamate,5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid, and HATU were reacted to give 150 as a white solid (30 mg, 32%)over two steps. ¹H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 7.64-7.36 (m,4H), 7.29 (t, J=8.7, 2H), 3.56 (s, 3H), 3.46-3.31 (m, 2H), 3.13 (t,J=15.2, 2H), 1.93 (s, 1H), 1.41 (s, 2H). ESIMS m/z=431.1 (M+1)

Example 1513-amino-N-(5-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide151

Following the procedures for Example 141, tert-butyl3-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-ylcarbamateand 3-amino-6-bromopicolinic acid were coupled and the intermediateamide was reacted with 2-fluorophenylboronic acid under palladiumcatalyzed Suzuki conditions to give 151 as a white solid (32 mg, 35%)over three steps. ¹H NMR (400 MHz, DMSO) δ 9.69 (s, 1H), 8.06 (t, J=7.8,1H), 7.75 (d, J=8.5, 1H), 7.66-7.25 (m, 5H), 7.06 (s, 2H), 3.59 (s, 3H),3.40 (t, J=10.6, 2H), 3.17 (d, J=8.5, 2H), 2.09 (s, 1H), 1.44 (s, 2H).ESIMS m/z=408.1 (M+1)

Example 1523-amino-N-(5-(4-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-chloropyrazine-2-carboxamide152

Following the procedures as described in Example 113, tert-butylcarbamate of 1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-4-amine wasconverted to 152 as a white solid (2.0 mg, 19%) over two steps. ESIMSm/z=351.1 (M+1)

Example 1545-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-o-tolyl-1H-pyrazol-4-yl)thiazole-4-carboxamide154

Following the procedures as described in Example 2 and starting with1-methyl-5-O— tolyl-1H-pyrazol-4-amine, 154 was obtained as a whitesolid (33 mg, 19%) over two steps. ¹H NMR (400 MHz, DMSO) δ 8.37 (s,1H), 7.88 (s, 1H), 7.54-7.39 (m, 5H), 7.39-7.28 (m, 2H), 7.21 (t, J=8.8,2H), 3.57 (d, J=7.0, 3H), 2.14 (s, 3H). ESIMS m/z=426.1 (M+1)

Example 1553-amino-6-(2-fluorophenyl)-N-(1-methyl-5-o-tolyl-1H-pyrazol-4-yl)picolinamide155

Following the procedures as described in Example 2 and starting with1-methyl-5-O— tolyl-1H-pyrazol-4-amine and 3-amino-6-bromopicolinicacid, 155 was obtained as a white solid (33 mg, 31%) over three steps.¹H NMR (400 MHz, DMSO) δ 9.58 (s, 1H), 8.06 (s, 1H), 7.71 (dd, J=8.8,2.1, 1H), 7.53 (ddd, J=16.4, 10.9, 4.9, 2H), 7.45-7.33 (m, 4H), 7.24(ddd, J=22.7, 13.7, 7.7, 3H), 7.08 (s, 2H), 3.63 (s, 3H), 2.15 (s, 3H).ESIMS m/z=402.1 (M+1)

Example 1563-amino-N-(5-(3-aminophenyl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide156

Following the procedures as described in Example 2 and starting withtert-butyl 3-(4-amino-1-methyl-1H-pyrazol-5-yl)phenylcarbamate and3-amino-6-bromopicolinic acid, 156 was obtained as a white solid (44 mg,42%) over three steps. ¹H NMR (400 MHz, DMSO) δ 9.95 (s, 1H), 8.09 (s,1H), 7.73 (dd, J=13.6, 4.7, 2H), 7.39 (dd, J=13.1, 5.4, 1H), 7.37-7.21(m, 4H), 7.12 (s, 2H), 6.82-6.60 (m, 3H), 5.43 (s, 2H), 3.77 (s, 3H).ESIMS m/z=403.1 (M+1)

Example 1575-amino-N-(5-(3-aminophenyl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide157

Following the procedures as described in Example 2 and starting withtert-butyl 3-(4-amino-1-methyl-1H-pyrazol-5-yl)phenylcarbamate, 157 wasobtained as a white solid (13 mg, 7.6%) over two steps. ¹H NMR (400 MHz,DMSO) δ 8.69 (s, 1H), 7.90 (s, 1H), 7.56-7.45 (m, 3H), 7.21 (dt, J=15.5,8.3, 3H), 6.72-6.54 (m, 3H), 5.28 (s, 2H), 3.74 (s, 3H). ESIMS m/z=427.1(M+1)

Table 2 Formula I Compounds 158-390 Example 158(S)-3-amino-N-(5-(3-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide158

Following the procedures as described in Example 23 and starting withtert-butyl azepan-3-ylcarbamate and 3-amino-6-bromopicolinic acid, 158was obtained as a white solid (3.8 mg, 4%) over three steps. ESIMSm/z=424.1 (M+1).

Example 159(R)-5-amino-N-(5-(3-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide159

Following the procedures as described in Examples 1 and 2, starting withtert-butyl azepan-3-ylcarbamate, 159 was obtained as a white solid (4.1mg, 3%) over two steps. ESIMS m/z=448.1 (M+1).

Example 160(R)-3-amino-N-(5-(3-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide160

Following the procedures as described in Example 23 and starting withtert-butyl azepan-3-ylcarbamate and 3-amino-6-bromopicolinic acid, 160was obtained as a white solid (4.5 mg, 5%) over three steps. ESIMSm/z=424.1 (M+1).

Example 161(S)-5-amino-N-(5-(3-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide161

Following the procedures as described in Examples 1 and 2, starting withtert-butyl azepan-3-ylcarbamate, 161 was obtained as a white solid (2.2mg, 2%) over two steps. ESIMS m/z=448.1 (M+1).

Example 1625-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(piperazin-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

Following the procedures as described in Examples 1 and 2, starting withtert-butyl piperazine-1-carboxylate, 162 was obtained as a white solid(36 mg, 20%) over two steps. ¹H NMR (400 MHz, DMSO) δ 8.72 (s, 1H),7.61-7.46 (m, 3H), 7.41 (s, 1H), 7.27 (t, J=8.7 Hz, 2H), 3.64 (s, 3H),3.02-2.91 (m, 4H), 2.82-2.74 (m, 4H). ESIMS m/z=420.1 (M+1).

Example 1633-amino-6-(2-fluorophenyl)-N-(1-methyl-5-(piperazin-1-yl)-1H-pyrazol-4-yl)picolinamide

Following the procedures as described in Example 23 and starting withtert-butyl piperazine-1-carboxylate, 163 was obtained as a white solid(19 mg, 21%) over two steps. ¹H NMR (400 MHz, DMSO) δ 9.81 (s, 1H),8.25-8.06 (m, 1H), 7.76 (dd, J=8.8, 2.3 Hz, 1H), 7.54 (s, 1H), 7.42 (dd,J=13.0, 5.6 Hz, 1H), 7.31 (tt, J=11.0, 5.6 Hz, 3H), 7.08 (s, 2H), 6.52(s, 1H), 3.68 (s, 3H), 3.19-3.02 (m, 4H), 2.92 (s, 4H). ESIMS m/z=396.1(M+1).

Example 164N-(5-(1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxamide

Following the procedures as described in Examples 1 and 2, starting withtert-butyl 1,4-diazepane-1-carboxylate, 164 was obtained as a whitesolid (36 mg, 20%) over two steps. ¹H NMR (400 MHz, DMSO) δ 7.90 (s,1H), 7.65-7.44 (m, 3H), 7.29 (t, J=8.8 Hz, 2H), 3.62 (d, J=10.5 Hz, 3H),3.16 (t, J=6.0 Hz, 4H), 2.95 (t, J=6.1 Hz, 2H), 2.83 (t, J=5.6 Hz, 2H),1.48 (s, 2H). ESIMS m/z=434.1 (M+1).

Example 1655-amino-2-(2,6-difluorophenyl)-N-(1-ethyl-1H-pyrazol-4-yl)thiazole-4-carboxamide165

Following procedures from Examples 113 and shown in FIG. 5,tert-butyl-2-(2,6-difluorophenyl)-4-(1-ethyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5ylcarbamate was converted to 165: ¹H NMR (400 MHz, DMSO) δ 9.70 (s, 1H),7.99 (s, 1H), 7.64 (s, 1H), 7.56 (t, J=7.5 Hz, 1H), 7.50 (s, 2H), 7.27(t, J=8.4 Hz, 2H), 4.08 (q, J=7.2 Hz, 2H), 1.35 (t, J=8.0 Hz 3H); MS(ESI) m/z: 350[M+H⁺]

Example 1685-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(1H-pyrrolo[3,4-c]pyridin-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide168

Following the procedures as described in Examples 1 and 2, starting withtert-butyl hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate, 168was obtained as a white solid (34 mg, 31%) over two steps. ¹H NMR (400MHz, DMSO) δ 8.63 (s, 1H), 7.56-7.42 (m, 4H), 7.26 (t, J=8.7 Hz, 2H),3.63 (s, 3H), 3.39-3.33 (m, 2H), 3.23-3.17 (m, 1H), 3.09 (dd, J=8.6, 3.9Hz, 1H), 2.90-2.68 (m, 4H), 2.30 (s, 2H), 1.59 (d, J=5.3 Hz, 2H). ESIMSm/z=460.1 (M+1).

Example 1695-amino-2-(2-fluorophenyl)-N-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide169

Following procedures from Examples 141 and shown in FIG. 5,tert-butyl-2-(2-fluorophenyl)-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5ylcarbamate was converted to 169: ¹H NMR (400 MHz, DMSO) δ 9.86 (s, 1H),8.39 (t, J=7.8 Hz, 1H), 7.98 (s, 1H), 7.64 (s, 1H), 7.43 (m, 3H), 7.35(dd, J=13.5, 5.8 Hz, 2H), 3.82 (s, 3H); MS (ESI) m/z: 318 [M+H⁺]

Example 1705-amino-2-(2-fluorophenyl)-N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide170

Following procedures from Examples 141 and shown in FIG. 5, tert-butyl2-(2-fluoro-phenyl)-4-(1-(piperidin-4-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamatewas converted to 170: ¹H NMR (400 MHz, DMSO) δ 9.85 (s, 1H), 8.39 (m,1H), 8.00 (s, 1H), 7.68 (s, 1H), 7.44 (d, J=8.7 Hz, 3H), 7.40-7.30 (m,2H), 4.16 (m, 1H), 3.04 (d, J=12.6 Hz, 2H), 2.60 (t, J=11.3 Hz, 2H),1.95 (d, J=11.5 Hz, 2H), 1.75 (dd, J=11.9, 3.9 Hz, 2H); MS (ESI) m/z:387[M+H⁺]

Example 1725-amino-2-(2,6-difluorophenyl)-N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide172

Following procedures from Examples 116 and shown in FIG. 5, tert-butyl2-(2,6-difluorophenyl)-4-(1-(piperidin-4-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamatewas converted to 172: ¹H NMR (400 MHz, DMSO) δ 9.71 (s, 1H), 8.29 (s,1H), 7.99 (s, 1H), 7.68 (s, 1H), 7.56 (m, 1H), 7.50 (s, 2H), 7.27 (t,J=8.4 Hz, 2H), 4.26-4.10 (m, 1H), 3.11 (d, J=12.5 Hz, 2H), 2.68 (d,J=10.2 Hz, 2H), 1.96 (m, 2H), 1.83 (m, 2H); MS (ESI) m/z: 405[M+H⁺]

Example 1735-amino-N-(1-ethyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide173

Following procedures from Examples 141 and shown in FIG. 5,tert-butyl-2-(2-fluoro-phenyl)-4-(1-ethyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5ylcarbamate was converted to 173: ¹H NMR (400 MHz, DMSO) δ 9.91 (s, 1H),8.41 (td, J=7.8, 1.6 Hz, 1H), 8.02 (s, 1H), 7.66 (s, 1H), 7.49-7.40 (m,3H), 7.36 (dd, J=13.0, 7.0 Hz, 2H), 4.11 (q, J=7.3 Hz, 2H), 1.35 (t,J=8.0 Hz 3H); MS (ESI) m/z: 332[M+H⁺]

Example 1745-amino-2-(2-fluorophenyl)-N-(1-isopropyl-1H-pyrazol-4-yl)thiazole-4-carboxamide174

Following procedures from Examples 141 and shown in FIG. 5,tert-butyl-2-(2-fluorophenyl)-4-(1-isopropyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5ylcarbamate was converted to 174: ¹H NMR (400 MHz, DMSO) δ 9.90 (s, 1H),8.41 (td, J=7.8, 1.6 Hz, 1H), 8.03 (s, 1H), 7.66 (s, 1H), 7.48-7.41 (m,3H), 7.36 (dd, J=13.6, 6.7 Hz, 2H), 4.47 (dt, J=13.3, 6.7 Hz, 1H), 1.41(d, J=6.7 Hz, 6H); MS (ESI) m/z: 346[M+H⁺]

Example 1755-amino-2-(2,6-difluorophenyl)-N-(1-isopropyl-1H-pyrazol-4-yl)thiazole-4-carboxamide175

Following procedures from Examples 113 and shown in FIG. 5,tert-butyl-2-(2,6-difluorophenyl)-4-(1-isopropyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5ylcarbamate was converted to 175: ¹H NMR (400 MHz, DMSO) δ 9.74 (s, 1H),8.01 (s, 1H), 7.65 (s, 1H), 7.60-7.51 (m, 3H), 7.28 (t, J=8.0 Hz 2H),4.44 (dt, J=13.3, 6.7 Hz, 1H), 1.39 (d, J=6.7 Hz, 6H); MS (ESI) m/z:364[M+H⁺]

Example 1765-amino-2-(2,6-difluorophenyl)-N-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide176

Following procedures from Examples 113 and shown in FIG. 5,tert-butyl-2-(2,6-difluorophenyl)-4-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamatewas converted to 176: ¹H NMR (400 MHz, DMSO) δ 9.75 (s, 1H), 8.04 (s,1H), 7.66 (s, 1H), 7.61-7.49 (m, 3H), 7.27 (t, J=8.3 Hz, 2H), 4.75 (m,1H), 3.12 (dd, J=11.4, 7.0 Hz, 1H), 2.99 (dd, J=17.9, 7.4 Hz, 1H), 2.86(m, 2H), 2.14 (tt, J=17.7, 8.8 Hz, 1H), 1.98 (dd, J=12.9, 5.4 Hz, 1H);MS (ESI) m/z: 391[M+H⁺]

Example 1775-amino-2-(2-fluorophenyl)-N-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide177

Following procedures from Examples 141 and shown in FIG. 5,tert-butyl-2-(2-fluoro-phenyl)-4-(1-(pyrrolidin3-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamatewas converted to 177: ¹H NMR (400 MHz, DMSO) δ 9.91 (s, 1H), 8.41 (t,J=7.9 Hz, 1H), 8.07 (s, 1H), 7.67 (s, 1H), 7.44 (m, 3H), 7.36 (dd,J=13.6, 7.0 Hz, 2H), 4.78 (m, 1H), 3.14 (dd, J=11.4, 6.9 Hz, 1H),3.06-2.97 (m, 1H), 2.93 (dd, J=11.4, 4.4 Hz, 1H), 2.86 (dd, J=15.8, 9.3Hz, 1H), 2.24-2.10 (m, 1H), 1.98 (td, J=12.7, 5.2 Hz, 1H); MS (ESI) m/z:373[M+H⁺]

Example 1785-amino-N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide178

Following procedures from Examples 141 and shown in FIG. 5,tert-butyl-4-(1-cyclo-propylmethyl)-1H-pyrazol-4-ylcarbamoyl)2-(2-fluorophenyl)thiazol-5-ylcarbamate was converted to 178: ¹H NMR(400 MHz, DMSO) δ 9.89 (s, 1H), 8.41 (t, J=7.5 Hz, 1H), 8.07 (s, 1H),7.66 (s, 1H), 7.44 (s, 3H), 7.36 (dd, J=13.6, 6.1 Hz, 2H), 3.95 (d,J=7.1 Hz, 2H), 1.21 (m, 1H), 0.54 (q, J=5.7 Hz, 2H), 0.36 (q, J=4.8 Hz,2H); MS (ESI) m/z: 358[M+H⁺]

Example 1795-amino-N-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide179

Following procedures from Examples 113 and shown in FIG. 5,tert-butyl-4-(1-cyclo-propylmethyl)-1H-pyrazol-4-ylcarbamoyl)2-(2,6-difluorophenyl)thiazol-5 ylcarbamate was converted to 179: ¹H NMR(400 MHz, DMSO) δ 9.73 (s, 1H), 8.05 (s, 1H), 7.64 (s, 1H), 7.61-7.53(m, 1H), 7.51 (m, 2H), 7.27 (t, J=8.4 Hz, 2H), 3.92 (d, J=7.1 Hz, 2H),1.26-1.12 (m, 1H), 0.52 (q, J=5.8 Hz, 2H), 0.34 (q, J=4.7 Hz, 2H); MS(ESI) m/z: 376[M+H⁺]

Example 180(R)-5-amino-2-(2,6-difluorophenyl)-N-(1-(piperidin-3-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide180

Following procedures from Examples 113 and shown in FIG. 5,(R)-tert-butyl2-(2,6-difluorophenyl)-4-(1-(piperidin-3-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamatewas converted to 180: ¹H NMR (400 MHz, DMSO) δ 9.70 (s, 1H), 8.01 (s,1H), 7.66 (s, 1H), 7.60-7.52 (m, 1H), 7.51 (m, 2H), 7.27 (t, J=8.4 Hz,2H), 4.06 (t, J=10.4 Hz, 1H), 3.13 (d, J=12.0 Hz, 1H), 2.85 (d, J=11.6Hz, 1H), 2.74-2.64 (m, 1H), 2.43 (d, J=11.3 Hz, 1H), 2.05 (m, 1H),1.88-1.75 (m, 1H), 1.69 (d, J=12.8 Hz, 1H), 1.48 (d, J=12.2 Hz, 1H); MS(ESI) m/z: 405[M+H⁺]

Example 182(S)-5-amino-2-(2,6-difluorophenyl)-N-(1-(piperidin-3-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide182

Following procedures from Examples 113 and shown in FIG. 5,(S)-tert-butyl2-(2,6-difluorophenyl)-4-(1-(piperidin-3-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamatewas converted to 182: ¹H NMR (400 MHz, DMSO) δ 9.70 (s, 1H), 8.01 (s,1H), 7.66 (s, 1H), 7.56 (dt, J=13.7, 5.8 Hz, 1H), 7.52 (d, J=11.6 Hz,2H), 7.27 (t, J=8.4 Hz, 2H), 4.06 (t, J=10.4 Hz, 1H), 3.13 (d, J=11.5Hz, 1H), 2.85 (d, J=12.4 Hz, 1H), 2.73-2.63 (m, 1H), 2.43 (d, J=11.8 Hz,1H), 2.05 (m, 1H), 1.81 (m, 1H), 1.69 (d, J=12.8 Hz, 1H), 1.55-1.39 (m,1H); MS (ESI) m/z: 405[M+H⁺]

Example 1835-amino-2-(2,6-difluorophenyl)-N-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide183

Following procedures from Examples 113 and shown in FIG. 5, tert-butyl2-(2,6-di-fluorophenyl)-4-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamatewas converted to 183: ¹H NMR (400 MHz, DMSO) δ 9.72 (s, 1H), 8.01 (s,1H), 7.63 (dd, J=11.7, 5.1 Hz, 1H), 7.60-7.53 (m, 1H), 7.51 (d, J=6.1Hz, 2H), 7.27 (t, J=8.4 Hz, 2H), 4.13 (t, J=6.5 Hz, 2H), 2.61 (t, J=6.5Hz, 2H), 2.53-2.16 (s, 6H); MS (ESI) m/z: 393[M+H⁺]

Example 1845-amino-2-(2,6-difluorophenyl)-N-(1,5-dimethyl-1H-pyrazol-4-yl)thiazole-4-carboxamide184

Following procedures from Examples 113 and shown in FIG. 5,tert-butyl-2-(2,6-di-fluorophenyl)-4-(1,5-dimethyl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamatewas converted to 184: ¹H NMR (400 MHz, DMSO) δ 8.84 (s, 1H), 7.54-7.51(m, 1H), 7.48 (s, 2H), 7.44 (s, 1H), 7.27 (t, J=8.6 Hz, 2H), 3.71 (s,3H), 2.16 (s, 3H); MS (ESI) m/z: 350[M+H⁺]

Example 185N-(5-(4-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide185

Following procedures as in Example 141,6-(2-fluorophenyl)-pyrazine-2-carboxylic acid was converted to 185:¹H-NMR (DMSO, 500 MHz) δ (ppm): 10.02 (s, 1H), 9.31 (d, J=2.5 Hz, 1H),9.21 (s, 1H), 8.35-8.36 (m, 1H), 7.51-7.52 (m, 1H), 7.44-7.48 (m, 3H),3.65 (s, 3H), 3.02-3.11 (m, 4H), 2.62 (m, 1H), 1.74-1.77 (m, 2H),1.35-1.37 (m, 2H); MS (ESI) m/z: 396 [M+H⁺]

Example 1865-amino-2-(2,6-difluorophenyl)-N-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)thiazole-4-carboxamide186

Following procedures from Examples 113 and shown in FIG. 5, tert-butyl2-(2,6-di-fluorophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)thiazole-5-ylcarbamatewas converted to 186: ¹H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 7.60-7.50(m, 1H), 7.46 (s, 2H), 7.33-7.20 (m, 3H), 5.74 (s, 1H), 3.96 (t, J=6.0Hz, 2H), 3.19 (m, 2H), 2.02-1.93 (m, 2H); MS (ESI) m/z: 377[M+H⁺]

Example 1895-amino-2-(2,6-difluorophenyl)-N-(5-(4-hydroxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide189

Following procedures from Examples 113 and shown in FIG. 5, tert-butyl2-(2,6-difluorophenyl)-4-(5-(4-hydroxyazepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamatewas converted to racemic 189: ¹H NMR (400 MHz, DMSO) δ 8.64 (s, 1H),7.54 (s, 1H), 7.48 (m, 3H), 7.26 (t, J=8.3 Hz, 2H), 4.44 (d, J=3.7 Hz,1H), 3.82 (m, 1H), 3.64 (s, 3H), 3.25-3.11 (m, 2H), 3.04 (m, 2H), 1.86(t, J=10.3 Hz, 2H), 1.73-1.47 (m, 4H); MS (ESI) m/z: 449[M+H⁺]

Example 190(R)—N-(5-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide190

Following procedures as in Example 141,6-(2-fluorophenyl)-pyrazine-2-carboxylic acid was converted to 190:¹H-NMR (DMSO, 500 MHz) δ (ppm): 9.28-9.30 (m, 2H), 8.24-8.27 (m, 1H),7.58-7.63 (m, 2H), 7.34-7.45 (m, 2H), 3.78 (s, 3H), 3.22.-3.25 (m, 1H),3.07-3.14 (m, 2H), 2.82-2.94 (m, 2H), 1.96-1.92 (m, 1H), 1.84-1.82 (m,1H), 1.21-1.26 (m, 1H); MS (ESI) m/z: 396 [M+H⁺]

Example 191(S)—N-(5-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide191 Following procedures as in Example 141,6-(2-fluorophenyl)-pyrazine-2-carboxylic acid was converted to 191:¹H-NMR (DMSO, 500 MHz) δ (ppm): 9.28-9.30 (m, 2H), 8.24-8.27 (m, 1H),7.58-7.63 (m, 2H), 7.34-7.45 (m, 2H), 3.78 (s, 3H), 3.22.-3.25 (m, 1H),3.07-3.14 (m, 2H), 2.82-2.94 (m, 2H), 1.96-1.92 (m, 1H), 1.84-1.82 (m,1H), 1.21-1.26 (m, 1H); MS (ESI) m/z: 396 [M+H⁺] Example 192N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide192

Following procedures as in Example 141,6-(2-fluorophenyl)-pyrazine-2-carboxylic acid was converted to 192:¹H-NMR (DMSO, 500 MHz) δ (ppm): 10.07 (s, 1H), 9.30 (s, 1H), 9.22 (s,1H), 8.36 (s, 1H), 7.63 (s, 1H), 7.46-7.47 (m, 2H), 7.42 (s, 1H),7.26-7.30 (m, 2H), 4.13-4.34 (m, 3H), 3.46-3.47 (m, 2H), 3.36-3.37 (m,2H), 2.98-3.01 (m, 2H), 1.71-1.75 (m, 2H), 1.57-1.58 (m, 1H), 1.23-1.26(m, 2H); MS (ESI) m/z: 410 [M+H⁺]

Example 193N-(5-(4-(2-aminoethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide193

Following procedures as in Example 141,6-(2-fluorophenyl)-pyrazine-2-carboxylic acid was converted to 193:¹H-NMR (DMSO, 500 MHz) δ (ppm): 9.27-9.29 (m, 2H), 8.24-8.25 (m, 1H),7.60-7.61 (m, 2H), 7.34-7.45 (m, 2H), 3.75 (s, 3H), 3.15.-3.19 (m, 4H),2.79 (t, J=7 Hz, 2H), 1.79 (d, J=12.5 Hz, 2H), 1.38-1.54 (m, 5H); MS(ESI) m/z: 424 [M+H⁺]

Example 194N-(5-(1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide194 Following procedures as in Example 141,6-(2-fluorophenyl)-pyrazine-2-carboxylic acid was converted to 194: ¹HNMR (CD₃OD, 500 MHz) δ 9.27 (s, 1H), 9.22 (d, 1H), 8.10 (d, 1H), 7.92(s, 1H), 7.40 (m, 1H), 6.9 (m, 1H), 6.8 (m, 1H), 3.76 (s, 3H), 3.32-3.37(m, 4H), 3.30-3.92 (m, 4H), 1.79 (m, 2H); MS (ESI) m/z: 396 (M+1)Example 197(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide197

Following procedures as in Example 200,5-(tert-butoxy-carbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylicacid was converted to 197: ¹H-NMR (DMSO, 500 MHz) δ (ppm): 8.94 (s, 1H),8.22 (s, 1H), 7.35-7.51 (m, 6H), 3.65 (s, 3H), 3.04-3.15 (m, 5H), 1.82(m, 3H), 1.54 (m, 3H); MS (ESI) m/z: 430 [M+H⁺]

Example 198N-(5-(4-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-5-(2-fluorophenyl)nicotinamide198

Following procedures as in Example 141, 5-(2-fluorophenyl)-nicotinicacid was converted to 198: ¹H-NMR (DMSO, 500 MHz) δ (ppm): 9.82 (s, 1H),9.09 (s, 1H), 8.94 (s, 1H), 8.43 (s, 1H), 7.71-7.73 (m, 1H), 7.53-7.54(m, 1H), 7.38-7.43 (m, 2H), 7.27 (s, 1H), 3.57-3.64 (m, 3H), 3.00-3.07(m, 2H), 2.96-2.98 (m, 2H), 2.61-2.63 (m, 1H), 1.73-1.75 (m, 2H),1.33-1.35 (m, 2H); MS (ESI) m/z: 395 [M+H⁺]

Example 200(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,4-difluorophenyl)thiazole-4-carboxamide200 Step 1: Preparation of[(R)-1-(4-{[5-tert-butoxycarbonylamino-2-(2,4-difluoro-phenyl)-thiazole-4-carbonyl]-amino}-2-methyl-2H-pyrazol-3-yl)-perhydro-azepin-4-yl]-carbamicacid benzyl ester

In a microwave vial was placed((R)-1-{4-[(2-bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl)-amino]-2-methyl-2H-pyrazol-3-yl}-perhydro-azepin-4-yl)-carbamicacid benzyl ester (78.2 mg, 0.12 mmol),2-(2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (101.3mg, 0.42 mmol, 3.5 eq.), cesium carbonate (196.4 mg, 0.60 mmol, 5.0 eq),[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complexedwith dichloromethane (1:1) (29.5 mg, 0.036 mmol, 0.30 eq), and anhydrousN,N-dimethylformamide (3.5 mL). The reaction mixture was degassed withN₂ for 10 minutes and then subjected to microwave irradiation at 100° C.for 30 minutes. The reaction mixture was diluted with ethyl acetate (50mL) and then filtered through a pad of Celite. The filtrate was washedwith 50% brine/water, water and brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude was purified via flashcolumn chromatography eluted with 40 to 100% ethyl acetate/heptane togive 46.4 mg (56.5%) of desired product as a white solid. ¹H NMR (400MHz, CDCl₃) δ 10.35 (s, 1H), 8.63 (s, 1H), 8.14-8.04 (m, 1H), 7.82 (s,1H), 7.31 (s, 5H), 7.03-6.87 (m, 2H), 5.11-5.00 (s, 2H), 4.84-4.74 (m,1H), 3.95-3.85 (m, 1H), 3.74 (s, 3H), 3.35-3.24 (m, 2H), 3.23-3.11 (m,2H), 2.18-2.03 (m, 2H), 1.97-1.65 (m, 4H), 1.53 (s, 9H); MS (ESI) m/z:682.6 [M+H]⁺.

Step 2: Preparation of title compound5-amino-2-(2,4-difluoro-phenyl)-thiazole-4-carboxylic acid[5-((R)-4-amino-azepan-1-yl)-1-methyl-1H-pyrazol-4-yl]-amide

To a stirred mixture of[(R)-1-(4-{[5-tert-butoxycarbonylamino-2-(2,4-difluoro-phenyl)-thiazole-4-carbonyl]-amino}-2-methyl-2H-pyrazol-3-yl)-perhydro-azepin-4-yl]-carbamicacid benzyl ester (46.0 mg, 0.067 mmol) in anhydrous DCM (4.0 mL) at−10° C. under N₂ was added dropwise 1.0 M boron tribromide in DCM (0.22mL, 0.22 mmol, 3.3 eq.). The reaction mixture was stirred at ambienttemperature for 4 h and then cooled to −20° C. Additional 1.0 M Borontribromide in DCM (0.11 mL, 0.11 mmol, 1.65 eq.) was added dropwise, andthe reaction mixture was stirred at ambient temperature for 16 h. Thereaction mixture was quenched with saturated aq. NaHCO₃ solution andthen extracted with ethyl acetate (3×50 mL). The combined organic phaseswere washed with brine, dried over Na₂SO₄, filtered, and concentratedunder reduced pressure. The crude was purified via reverse phase HPLC toafford 200 (12.7 mg, 42.1%) as a white solid. ¹H NMR (400 MHz, DMSO) δ8.93 (s, 1H), 8.39 (s, 1H), 8.33 (dd, J=15.5, 8.8 Hz, 1H), 7.47-7.36 (m,4H), 7.29 (dd, J=11.6, 5.3 Hz, 1H), 3.66 (s, 3H), 3.26-3.14 (m, 3H),3.14-3.05 (m, 3H), 2.03-1.89 (m, 2H), 1.88-1.77 (m, 1H), 1.76-1.56 (m,3H); MS (ESI) m/z: 448.1 [M+H]+

Example 2015-amino-N-(5-(4-(2-aminoethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide201

Following procedures as in Example 141,5-(tert-butoxy-carbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid was converted to 201: ¹H-NMR (DMSO, 500 MHz) δ (ppm): 8.72 (s, 1H),8.45 (s, 1H), 7.52-7.55 (m, 3H), 7.43 (s, 1H), 7.26-7.30 (m, 2H), 3.59(s, 3H), 2.99-3.04 (m, 4H), 2.77-2.78 (m, 2H), 1.69-1.71 (m, 2H),1.43-1.51 (m, 3H), 1.21-1.27 (m, 2H); MS (ESI) m/z: 462 [M+H⁺]

Example 202(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluoro-4-methoxyphenyl)thiazole-4-carboxamide202 Step 1: Preparation of[(R)-1-(4-{[5-tert-butoxycarbonylamino-2-(2,6-difluoro-4-methoxyphenyl)-thiazole-4-carbonyl]-amino}-2-methyl-2H-pyrazol-3-yl)-perhydro-azepin-4-yl]-carbamicacid benzyl ester

Following the procedure as described in Example 258, step 1, using2-(2,6-difluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanein place of2-(2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,[(R)-1-(4-{[5-tert-butoxy-carbonylamino-2-(2,6-difluoro-4-methoxyphenyl)-thiazole-4-carbonyl]-amino}-2-methyl-2H-pyrazol-3-yl)-perhydro-azepin-4-yl]-carbamicacid benzyl ester was obtained in 11.9% yield. MS (ESI) m/z: 712.4[M+H⁺].

Step 2: A heterogeneous mixture of[(R)-1-(4-{[5-tert-butoxycarbonylamino-2-(2,6-difluoro-4-methoxyphenyl)-thiazole-4-carbonyl]-amino}-2-methyl-2H-pyrazol-3-yl)-perhydro-azepin-4-yl]-carbamicacid benzyl ester (14.5 mg, 0.02 mmol) and 2M aq. HCl (5 mL) was stirredat 100° C. under N₂ for 4 h. The resultant homogeneous reaction wascooled to RT and the water solvent was removed using toluene azeotrope.The crude was redissolved in 9:1 v/v DMF:MeOH (1 mL) and purified viareverse phase HPLC to afford 202 (9.2 mg, 94.3%) as a white solid. ¹HNMR (400 MHz, DMSO) δ 8.75 (broad s, 1H), 8.46 (s, 1H), 7.53 (s, 1H),7.42 (s, 2H), 6.95 (s, 1H), 6.92 (s, 1H), 3.85 (s, 3H), 3.64 (s, 3H),3.20-3.04 (m, 6H), 1.95-1.77 (m, 3H), 1.68-1.52 (m, 3H); MS (ESI) m/z:479.1 [M+H]+

Example 2035-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(4-(N-methylacetamido)azepan-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide203

Following procedures as in Example 141,5-(tert-butoxy-carbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid was converted to 203: ¹H-NMR (DMSO, 500 MHz) δ (ppm): 8.70 (s, 1H),7.49-7.55 (m, 4H), 7.26-7.29 (m, 2H), 3.66-3.67 (m, 3H), 3.21.-3.29 (m,2H), 3.06-3.08 (m, 2H), 2.70 (s, 2H), 2.57 (s, 3H), 1.90-1.96 (m, 3H),1.73-1.86 (m, 5H); MS (ESI) m/z: 504 [M+H⁺]

Example 2045-amino-N-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide204

Following procedures from Examples 113 and shown in FIG. 5, tert-butyl4-(1-(difluoromethyl)-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate was converted to 204: ¹H NMR (400 MHz, DMSO) δ 10.11 (s, 1H),8.40 (s, 1H), 8.03 (s, 1H), 7.79 (s, 1H), 7.60 (m, 3H), 7.28 (t, J=8 Hz,2H); MS (ESI) m/z: 372[M+H⁺]

Example 205(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide205 Step 1: Preparation of[(R)-1-(4-{[5-tert-butoxycarbonylamino-2-(3-trifluoromethyl-phenyl)-thiazole-4-carbonyl]-amino}-2-methyl-2H-pyrazol-3-yl)-perhydro-azepin-4-yl]-carbamicacid benzyl ester

In a microwave vial was placed((R)-1-{4-[(2-bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl)-amino]-2-methyl-2H-pyrazol-3-yl}-perhydro-azepin-4-yl)-carbamicacid benzyl ester (100.0 mg, 0.154 mmol),4,4,5,5-tetramethyl-2-(3-trifluoromethyl-phenyl)-1,3,2-dioxaborolane(209.7 mg, 0.77 mmol, 5.0 eq.), sodium carbonate (49.0 mg, 0.46 mmol,3.0 eq.), potassium acetate (45.4 mg, 0.46 mmol, 3.0 eq.),[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complexedwith dichloromethane (1:1) (25.2 mg, 0.03, mmol, 0.20 eq), ACN (9.0 mL),and water (1.9 mL). The reaction mixture was degassed with N₂ for 10minutes and then subjected to microwave irradiation at 100° C. for 40minutes. The reaction mixture was diluted with ethyl acetate (50 mL) andthen filtered through a pad of Celite. The filtrate was washed with 50%brine/water, water and brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude was purified via flashcolumn chromatography eluted with 50 to 100% ethyl acetate/heptane togive 73.5 mg (66.8%) of desired product as an oil. MS (ESI) m/z: 714.4[M+H]⁺.

Step 2: Preparation of title compound(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide

Following the procedure as in Example 202, step 2, using[(R)-1-(4-{[5-tert-butoxycarbonylamino-2-(3-trifluoromethyl-phenyl)-thiazole-4-carbonyl]-amino}-2-methyl-2H-pyrazol-3-yl)-perhydro-azepin-4-yl]-carbamicacid benzyl ester in place of[(R)-1-(4-{[5-tert-butoxycarbonylamino-2-(2,6-difluoro-4-methoxyphenyl)-thiazole-4-carbonyl]-amino}-2-methyl-2H-pyrazol-3-yl)-perhydro-azepin-4-yl]-carbamicacid benzyl ester, 205 was obtained in 64.4% yield as a white solid. ¹HNMR (400 MHz, DMSO) δ 8.98 (s, 1H), 8.21 (s, 1H), 8.04 (d, J=7.5 Hz,1H), 7.76-7.66 (m, 2H), 7.53 (broad s, 2H), 7.42 (s, 1H), 3.66 (s, 3H),3.40-3.10 (m, 7H), 1.99-1.78 (m, 3H), 1.73-1.55 (m, 3H); MS (ESI) m/z:480.1 [M+H]+

Example 206(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(4-(trifluoromethyl)phenyl)thiazole-4-carboxamide206 Step 1: Preparation of (R)-benzyl1-(4-(5-amino-2-(4-(trifluoromethyl)phenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate

Following the procedure as described in Example 205, step 1, using4,4,5,5-tetramethyl-2-(4-trifluoromethyl-phenyl)-1,3,2-dioxaborolane inplace of4,4,5,5-tetramethyl-2-(3-trifluoromethyl-phenyl)-1,3,2-dioxaborolane,(R)-benzyl1-(4-(5-amino-2-(4-(trifluoromethyl)phenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamatewas obtained in 67.0% yield. MS (ESI) m/z: 614.3 [M+H⁺].

Step 2: Preparation of title compound(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(4-(trifluoromethyl)phenyl)thiazole-4-carboxamide

Following the procedure as described in Example 200, Step 2, using(R)-benzyl1-(4-(5-amino-2-(4-(trifluoromethyl)phenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamatein place of[(R)-1-(4-{[5-tert-butoxycarbonylamino-2-(2,4-difluoro-phenyl)-thiazole-4-carbonyl]-amino}-2-methyl-2H-pyrazol-3-yl)-perhydro-azepin-4-yl]-carbamicacid benzyl ester, 206 was obtained in 25.2% yield. ¹H NMR (400 MHz,DMSO) δ 8.90 (s, 1H), 8.04 (d, J=8.1 Hz, 2H), 7.81 (d, J=8.2 Hz, 2H),7.58 (broad s, 2H), 7.42 (s, 1H), 3.66 (s, 3H), 3.60-3.05 (m, 7H),2.00-1.80 (m, 3H), 1.76-1.57 (m, 3H); MS (ESI) m/z: 480.1 [M+H⁺]

Example 208(R)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(4-(N-methylacetamido)azepan-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide208

Following procedures as in Example 141,5-(tert-butoxy-carbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid was converted to 208: ¹H-NMR (DMSO, 500 MHz) δ (ppm): 8.70 (s, 1H),7.49-7.55 (m, 4H), 7.26-7.29 (m, 2H), 3.66-3.67 (m, 3H), 3.21.-3.29 (m,2H), 3.06-3.08 (m, 2H), 2.70 (s, 2H), 2.57 (s, 3H), 1.90-1.96 (m, 3H),1.73-1.86 (m, 5H); MS (ESI) m/z: 504 [M+H⁺]

Example 2095-amino-N-(1-(2-aminoethyl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide209

Following procedures from Examples 113 and shown in FIG. 5, tert-butyl4-(1-(2-aminoethyl)-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamatewas converted to 209: ¹H NMR (400 MHz, DMSO) δ 9.74 (s, 1H), 8.26 (s,1H), 8.02 (s, 1H), 7.69 (s, 1H), 7.56-7.50 (m, 3H), 7.27 (t, J=8.4 Hz,2H), 4.09 (t, J=6.2 Hz, 2H), 2.97 (t, J=6.2 Hz, 2H); MS (ESI) m/z:365[M+H⁺]

Example 210(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-(trifluoromethyl)phenyl)thiazole-4-carboxamide210 Step 1: Preparation of[(R)-1-(4-{[5-tert-butoxycarbonylamino-2-(2-trifluoromethyl-phenyl)-thiazole-4-carbonyl]-amino}-2-methyl-2H-pyrazol-3-yl)-perhydro-azepin-4-yl]-carbamicacid benzyl ester

In a microwave vial was placed((R)-1-{4-[(2-bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl)-amino]-2-methyl-2H-pyrazol-3-yl}-perhydro-azepin-4-yl)-carbamicacid benzyl ester (132.7 mg, 0.205 mmol),4,4,5,5-tetramethyl-2-(2-trifluoromethyl-phenyl)-1,3,2-dioxaborolane(278.3 mg, 1.02 mmol, 5.0 eq.), sodium carbonate (65.0 mg, 0.61 mmol,3.0 eq.), potassium acetate (60.2 mg, 0.61 mmol, 3.0 eq.),[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complexedwith dichloromethane (1:1) (33.4 mg, 0.041, mmol, 0.20 eq), ACN (10 mL),and water (2.5 mL). The reaction mixture was degassed with N₂ for 10minutes and then subjected to microwave irradiation at 100° C. for 40minutes. The reaction mixture was diluted with ethyl acetate (50 mL) andthen filtered through a pad of Celite. The filtrate was washed with 50%brine/water, water and brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude was purified via flashcolumn chromatography eluted with 50 to 100% ethyl acetate/heptane togive 83.9 mg (57.4%) of desired product as a foam. MS (ESI) m/z: 714.4[M+H⁺].

Step 2: Preparation of title compound(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-(trifluoromethyl)phenyl)thiazole-4-carboxamide

A heterogeneous mixture of[(R)-1-(4-{[5-tert-butoxycarbonylamino-2-(2-trifluoromethyl-phenyl)-thiazole-4-carbonyl]-amino}-2-methyl-2H-pyrazol-3-yl)-perhydro-azepin-4-yl]-carbamicacid benzyl ester (83.9 mg, 0.117 mmol) in 1,4-dioxane (1.0 mL) and 2Maq. HCl (10 mL) was stirred at 120° C. under N₂ for 16 h. The resultanthomogeneous reaction was then slowly quenched with saturated aq. NaHCO₃solution and then extracted with ethyl acetate (3×50 mL). The combinedorganic phases were washed with brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude was purified via reversephase HPLC to afford 210 (33.4 mg, 59.2%) as a white solid. ¹H NMR (400MHz, DMSO) δ 8.51 (s, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.78 (d, J=4.1 Hz,2H), 7.68 (dd, J=8.1 Hz, 3.9 Hz, 1H), 7.58 (s, 1H), 7.46 (broad s, 2H),3.64 (s, 3H), 3.10 (t, J=5.3 Hz, 4H), 3.02-2.90 (m, 1H), 1.89-1.73 (m,3H), 1.64-1.44 (m, 3H); 2 protons buried in water peak; MS (ESI) m/z:480.1 [M+H⁺]

Example 211(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-4-methylphenyl)thiazole-4-carboxamide211

Following the procedures from Example 210 and shown in FIG. 3, using((R)-1-{4-[(2-bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl)-amino]-2-methyl-2H-pyrazol-3-yl}-perhydro-azepin-4-yl)-carbamicacid benzyl ester and 2-fluoro-4-methyl-phenylboronic acid as startingmaterials, 211 was obtained in 20.5% yield over two steps: ¹H NMR (400MHz, DMSO) δ 8.88 (s, 1H), 8.14 (t, J=8.2 Hz, 1H), 7.47 (s, 1H), 7.36(broad s, 2H), 7.22-7.14 (m, 2H), 3.66 (s, 3H), 3.45-3.05 (m, 7H), 2.36(s, 3H), 1.98-1.78 (m, 3H), 1.72-1.54 (m, 3H); MS (ESI) m/z: 444.2[M+H⁺]

Example 212(R)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-5-fluoro-6-(2-fluorophenyl)picolinamide212

Following procedures from Examples 141, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16was converted to 212. ¹H NMR (400 MHz, DMSO) δ 8.23 (dd, J=8.6, 3.8 Hz,1H), 8.09 (t, J=9.1 Hz, 1H), 7.81 (t, J=7.4 Hz, 1H), 7.67-7.55 (m, 2H),7.50-7.34 (m, 2H), 3.65 (s, 3H), 3.18-2.99 (m, 5H), 2.91 (t, J=8.7 Hz,1H), 1.85-1.62 (m, 3H), 1.61-1.34 (m, 3H). MS (ESI) m/z: 427.2 [M+H⁺].

Example 2145-amino-2-(2,6-difluorophenyl)-N-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide214

Following procedures from Examples 113 and shown in FIG. 5, tert-butyl2-(2,6-difluorophenyl)-4-(1-(2-(piperidin-1-yl)ethyl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamatewas converted to 214: ¹H NMR (400 MHz, DMSO) δ 9.71 (s, 1H), 8.00 (s,1H), 7.64 (s, 1H), 7.60-7.52 (m, 1H), 7.49 (s, 2H), 7.26 (t, J=8.4 Hz,2H), 4.14 (t, J=6.7 Hz, 2H), 2.64 (dd, J=14.1, 7.4 Hz, 2H), 2.41-2.31(m, 4H), 1.52-1.43 (m, 4H), 1.37 (d, J=5.1 Hz, 2H); MS (ESI) m/z:433[M+H⁺]

Example 2155-amino-2-(2,6-difluorophenyl)-N-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide215

Following procedures from Examples 113 and shown in FIG. 5, tert-butyl2-(2,6-difluorophenyl)-4-(1-(2-morpholinoethyl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate was converted to 215: ¹H NMR (400 MHz, DMSO) δ 9.71 (s, 1H),8.01 (s, 1H), 7.65 (s, 1H), 7.60-7.52 (m, 1H), 7.51 (d, J=10.0 Hz, 2H),7.27 (t, J=8.4 Hz, 2H), 4.17 (t, J=6.6 Hz, 2H), 3.58-3.51 (m, 4H), 2.68(t, J=6.6 Hz, 2H), 2.42-2.35 (m, 4H); MS (ESI) m/z: 435[M+H⁺]

Example 216(R)-5-amino-N-(5-(3-(2-aminoethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide216

Following procedures as in Example 141,5-(tert-butoxy-carbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid was converted to 216: ¹H-NMR (DMSO, 500 MHz) δ (ppm): 8.73 (s, 1H),7.50-7.55 (m, 4H), 7.27 (t, 7.2 Hz, 2H), 3.63 (s, 3H), 2.93-3.08 (m,3H), 2.66-2.72 (m, 1H), 2.53-2.60 (m, 2H), 1.64-1.82 (m, 3H), 1.50-1.62(m, 1H), 1.25-1.36 (m, 2H), 0.96-1.06 (m, 1H); MS (ESI) m/z: 462 [M+H⁺]

Example 217(S)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(2-(pyrrolidin-2-yl)ethylamino)-1H-pyrazol-4-yl)thiazole-4-carboxamide217

Following procedures as in Example 141,5-(tert-butoxy-carbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid was converted to 217: ¹H-NMR (CDCl₃, 500 MHz) δ (ppm): 8.49 (s,1H), 7.45 (s, 1H), 7.34-7.38 (m, 1H), 7.01-7.05 (m, 2H), 6.18 (s, 2H),3.75 (s, 3H), 3.15-3.27 (m, 3H), 3.03-3.07 (m, 1H), 2.89-2.94 (m, 1H),1.90-1.96 (m, 1H), 1.83-1.86 (d, 15 Hz, 1H), 1.74-1.79 (m, 2H),1.63-1.68 (m, 1H), 1.38-1.46 (m, 1H); MS (ESI) m/z: 448 [M+H⁺]

Example 2185-amino-N-(5-(azepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide218

Following procedures as in Example 113, tert-butyl4-(5-(azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamatewas converted to 218: ¹H NMR (400 MHz, DMSO) δ 8.62 (d, J=27.5 Hz, 1H),7.59 (s, 1H), 7.57-7.43 (m, 3H), 7.33-7.20 (m, 2H), 3.65 (s, 3H), 3.12(d, J=5.1 Hz, 4H), 1.66 (s, 8H); MS (ESI) m/z: 433.3 [M+H⁺]

Example 219(R)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide219

Following procedures as in Example 210,6-(2-fluorophenyl)-pyrazine-2-carboxylic acid was converted to 219:¹H-NMR (DMSO, 500 MHz) δ (ppm): 9.30 (s, 1H), 9.23 (s, 1H), 8.26-8.29(m, 1H), 7.63-7.65 (m, 1H), 7.58 (s, 1H), 7.45-7.49 (m, 2H), 3.67 (s,3H), 3.12-3.18 (m, 4H), 2.95-2.96 (m, 1H), 1.75-1.83 (m, 4H), 1.43-1.52(m, 4H); MS (ESI) m/z: 410 [M+H⁺]

Example 220(S)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide220

Following procedures as in Example 210,6-(2-fluorophenyl)-pyrazine-2-carboxylic acid was converted to 220:¹H-NMR (DMSO, 500 MHz) δ (ppm): 9.30 (s, 1H), 9.23 (s, 1H), 8.26-8.29(m, 1H), 7.63-7.65 (m, 1H), 7.58 (s, 1H), 7.45-7.49 (m, 2H), 3.67 (s,3H), 3.12-3.18 (m, 4H), 2.95-2.96 (m, 1H), 1.75-1.83 (m, 4H), 1.43-1.52(m, 4H); MS (ESI) m/z: 410 [M+H⁺]

Example 221(R)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(2-(pyrrolidin-2-yl)ethylamino)-1H-pyrazol-4-yl)thiazole-4-carboxamide221

Following procedures as in Example 141,5-(tert-butoxy-carbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid was converted to 221: ¹H-NMR (DMSO, 500 MHz) δ (ppm): 8.49 (s, 1H),7.45 (s, 1H), 7.34-7.38 (m, 1H), 7.01-7.05 (m, 2H), 6.18 (s, 2H), 3.75(s, 3H), 3.15-3.27 (m, 3H), 3.03-3.07 (m, 1H), 2.89-2.94 (m, 1H),1.90-1.96 (m, 1H), 1.83-1.86 (d, 15 Hz, 1H), 1.74-1.79 (m, 2H),1.63-1.68 (m, 1H), 1.38-1.46 (m, 1H); MS (ESI) m/z: 448 [M+H⁺]

Example 222(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(4-cyclopropyl-2-fluorophenyl)thiazole-4-carboxamide222

Following the procedures from Example 210 and shown in FIG. 3, using((R)-1-{4-[(2-bromo-5-tert-butoxycarbonylamino-thiazole-4-carbonyl)-amino]-2-methyl-2H-pyrazol-3-yl}-perhydro-azepin-4-yl)-carbamicacid benzyl ester and2-(4-cyclopropyl-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneas starting materials, 222 was obtained in 37.8% yield over two steps:¹H NMR (400 MHz, DMSO) δ 8.86 (s, 1H), 8.10 (t, J=8.2 Hz, 1H), 7.53 (s,1H), 7.35 (s, 2H), 7.06 (dd, J=19.7, 10.7 Hz, 2H), 3.65 (s, 3H),3.21-2.99 (m, 5H), 2.05-1.95 (m, 1H), 1.90-1.73 (m, 4H), 1.65-1.47 (m,3H), 1.06-0.99 (m, 2H), 0.81-0.75 (m, 2H); MS (ESI) m/z: 470.2 [M+H]+

Example 223(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide223

Following procedures from Example 141, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16was converted to 223: ¹H NMR (400 MHz, DMSO) δ 8.90 (s, 1H), 8.03 (d,J=7.6 Hz, 1H), 7.51 (s, 1H), 7.39 (s, 2H), 7.23 (d, J=9.0 Hz, 2H), 3.65(s, 3H), 3.19-3.04 (m, 6H), 2.37 (s, 3H), 1.84 (m, 3H), 1.56 (m, 3H). MS(ESI) m/z: 444.2 [M+H⁺]

Example 224(S)-5-amino-2-(2,6-difluorophenyl)-N-(5-(4-(dimethylamino)azepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide224

Following procedures as in Example 141,5-(tert-butoxy-carbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid was converted to 224: ¹H-NMR (DMSO, 500 MHz) δ (ppm): 7.57 (s, 1H),7.47-7.50 (m, 1H), 7.14-7.17 (m, 2H), 3.75 (s, 3H), 3.36-3.40 (m, 3H),3.24-3.27 (m, 2H), 2.68 (s, 6H), 1.80-2.11 (m, 6H); MS (ESI) m/z: 476[M+H H⁺]

Example 225(R)-5-amino-2-(2,6-difluorophenyl)-N-(5-(4-(dimethylamino)azepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide225

Following procedures as in Example 141,5-(tert-butoxy-carbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid was converted to 225: ¹H-NMR (DMSO, 500 MHz) δ (ppm): ¹H-NMR (DMSO,500 MHz) δ (ppm): 7.57 (s, 1H), 7.50-7.47 (m, 1H), 7.17-7.14 (m, 2H),3.75 (s, 3H), 3.40-3.36 (m, 3H), 3.27-3.24 (m, 2H), 2.68 (s, 6H),2.11-1.80 (m, 6H); MS (ESI) m/z: 476 [M+H⁺]

Example 226(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide226

Following procedures as in Example 200,5-(tert-butoxy-carbonylamino)-2-(2,5-difluorophenyl)thiazole-4-carboxylicacid was converted to 226: ¹H-NMR (DMSO, 500 MHz) δ (ppm): 9.11 (s, 1H),7.57 (s, 1H), 8.11-8.12 (m, 1H), 7.40-7.48 (m, 3H), 7.27-7.29 (m, 1H),3.65 (s, 3H), 3.08-3.18 (m, 4H), 2.95-3.01 (m, 1H), 1.75-1.83 (m, 3H),1.39-1.58 (m, 3H); MS (ESI) m/z: 448 [M+H⁺]

Example 227(R)—N-(5-(4-acetamidoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxamide227

In a 40 mL sealed vial was added (R)-tert-butyl4-(5-(4-Cbz-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate(220 mg, 0.32 mmol, prepared according to Example 140 Step 1),1,4-cyclohexadiene (0.18 mL, 1.94 mmol) and ethanol (12 mL). 10% Pd/C(35.0 mg, 0.033 mmol) was added and the reaction vial was vacuum purgedwith nitrogen three times. The reaction mixture was then stirred at 95°C. under nitrogen for 2 h. After cooling down to room temperature, thereaction mixture was filtered through Celite and rinsed thoroughly withmethanol. The solvent was distilled off under reduced pressure to givethe crude product (R)-tert-butyl4-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate(180 mg, 84%).

In a 50 mL round bottom flask was added the above product (148 mg, 0.27mmol), acetic acid (0.02 mL, 0.35 mmol) and HATU (0.308 mg, 0.81 mmol).Methylene chloride (6 mL) and diisopropylethylamine (0.33 mL, 1.89 mmol)were added and the reaction mixture was stirred at room temperature for2 h upon which the reaction was complete by LCMS. The solvent wasdistilled off and the crude material was purified via flashchromatography, methylene chloride/methanol (with 1% ammonium hydroxide)0% to 10% to afford (R)-tert-butyl4-(5-(4-acetamidoazepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate(17 mg, 11%).

The above product (17 mg, 0.03 mmol) was stirred with 4.0M HCl indioxane at room temperature overnight. The reaction was monitored byLCMS. Upon completion of the reaction, the solvent was distilled off andthe residue was basified with saturated sodium bicarbonate. The aqueoussolution was extracted with ethyl acetate 3×. The combined organiclayers were dried over sodium sulfate, filtered and concentrated. Thecrude product was purified via reverse phase HPLC to afford 227 (5.9 mg,42%). ¹H NMR (400 MHz, DMSO) δ 8.66 (s, 1H), 7.74 (d, J=7.5 Hz, 1H),7.50 (d, J=19.7 Hz, 4H), 7.26 (t, J=8.7 Hz, 2H), 3.84 (s, 1H), 3.66 (s,3H), 3.14 (m, 5H), 1.96-1.79 (m, 3H), 1.76 (s, 3H), 1.72-1.51 (m, 3H).MS (ESI) m/z: 490.2 [M+H⁺].

Example 2285-amino-N-(5-(3-(2-aminoethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide228 Following procedures as in Example 141,5-(tert-butoxy-carbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid was converted to 228: ¹H-NMR (DMSO, 500 MHz) δ (ppm): 8.73 (s, 1H),7.50-7.55 (m, 4H), 7.27 (t, 7.2 Hz, 2H), 3.64 (s, 3H), 2.93-3.08 (m,3H), 2.68-2.72 (m, 1H), 2.54-2.66 (m, 2H), 1.64-1.82 (m, 3H), 1.50-1.62(m, 1H), 1.28-1.42 (m, 2H), 0.96-1.08 (m, 1H); MS (ESI) m/z: 462 [M+H⁺]Example 229(R)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-5-fluoro-6-phenylpicolinamide229

Following procedures from Example 141, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16was converted to (R)-benzyl1-(4-(5-fluoro-6-phenylpicolinamido)-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate.

In a 40 mL sealed vial was added (R)-benzyl1-(4-(5-fluoro-6-phenylpicolinamido)-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate(62 mg, 0.11 mmol), 1,4-cyclohexadiene (0.11 mL, 1.14 mmol) and ethanol(7 mL). 10% Pd/C (18.2 mg, 0.017 mmol) was added and the reaction vialwas vacuum purged with nitrogen three times. The reaction mixture wasthen stirred at 95° C. under nitrogen for 2 h. After cooling down toroom temperature, the reaction mixture was filtered through Celite andrinsed thoroughly with methanol. The solvent was distilled off underreduced pressure to give the crude product which was purified viareverse phase HPLC to afford 229. ¹H NMR (400 MHz, DMSO) δ 8.40 (s, 1H),8.18-7.98 (m, 4H), 7.68-7.48 (m, 3H), 3.68 (s, 3H), 3.25-3.03 (m, 5H),2.02-1.75 (m, 3H), 1.74-1.51 (m, 3H). MS (ESI) m/z: 409.2 [M+H⁺].

Example 2305-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-((tetrahydro-2H-pyran-4-yl)methoxy)-1H-pyrazol-4-yl)thiazole-4-carboxamide230 Step 1:1-Methyl-4-nitro-5-((tetrahydro-2H-pyran-4-yl)methoxy)-1H-pyrazole

To a solution of 5-chloro-1-methyl-4-nitro-1H-pyrazole (0.2 g, 1.24mmol) and tetrahydro-2H-pyran-4-yl-methanol (0.223 g, 1.92 mmol) in DMF(20 mL) cooled to 0° C. was added sodium hydride (60% dispersion inmineral oil, 0.128 g, 3.2 mmol) portionwise. The mixture was warmed toroom temperature and stirred for 1 hr. The mixture was concentratedunder reduced pressure and the residue dissolved in EtOAc. The organiclayer was washed with water, separated and passed through a phaseseparator cartridge. The solvent was removed under reduced pressure andthe crude product was purified via silica gel column chromatography(0-80% EtOAc/isohexane) to give1-methyl-4-nitro-5-((tetrahydro-2H-pyran-4-yl)methoxy)-1H-pyrazole as aclear oil (143 mg, 48%). ¹H NMR (400 MHz, CDCl₃) δ 7.98 (s, 1H), 4.28(d, J=6.3 Hz, 2H), 4.07-3.96 (m, 4H), 3.71 (s, 3H), 2.22-2.09 (m, 1H),1.82-1.62 (m, 4H)

Step 2: A solution of1-methyl-4-nitro-5-((tetrahydro-2H-pyran-4-yl)methoxy)-1H-pyrazole(0.143 g, 0.59 mmol) in MeOH (15 mL) was passed through the H-Cube® (70bar, 60° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solventwas removed under reduced pressure to afford the crude amine as a brownoil (0.115 g, 0.54 mmol). To a solution of this amine in DCM (8 mL) wasadded5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid (0.206 g, 0.58 mmol), HATU (0.615 g, 1.62 mmol) and DIPEA (0.66 mL,3.78 mmol). The mixture was stirred at room temperature for 18 hr. Water(30 ml) was added and stirring continued for 15 min. The layers wereseparated and the aqueous extracted with DCM. The combined organics werepassed through a phase separation cartridge and the solvent removedunder reduced pressure. Purification of the residue via silica gelcolumn chromatography (0-100% EtOAc/isohexane) gave tert-butyl2-(2,6-difluorophenyl)-4-(1-methyl-5-((tetrahydro-2H-pyran-4-yl)methoxy)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateas a yellow solid (0.22 g, 69%). This solid (0.129 g, 0.25 mmol) wasstirred in HCl in 1,4-dioxane (4.0 M, 4 mL) at room temperature for 18hr. The solvents were removed under reduced pressure and the cruderesidue was re-dissolved in MeOH and loaded onto an SCX column. Thecolumn was washed with MeOH and 0.3 M ammonia in MeOH to yield acoloured foam. Further purification via silica gel column chromatography(0-100% EtOAc/isohexane) gave 230 as a white solid (70 mg, 67%). ¹H NMR(400 MHz, CDCl₃) δ 8.26 (s, 1H), 7.62 (s, 1H), 7.37-7.28 (m, 1H),7.07-6.97 (m, 2H), 6.15 (s, 2H), 4.02 (d, J=6.5 Hz, 2H), 3.96 (dd,J=11.5, 4.5 Hz, 2H), 3.69 (s, 3H), 3.43-3.35 (m, 2H), 2.11-1.98 (m, 1H),1.75-1.69 (m, 2H), 1.51-1.38 (m, 2H). LCMS (ES+) m/z 450 (M+1)

Example 2315-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide231 Step 1:1-Methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,2,3,6-tetrahydropyridine

5-Chloro-1-methyl-4-nitro-1H-pyrazole (0.2 g, 1.24 mmol),1-methyl-1,2,3,6 tetrahydropyridine-4-boronic acid pinacol ester (0.553g, 2.48 mmol) and Pd(dppf)₂Cl₂ (0.02 g, 0.025 mmol) were suspended indegassed MeCN (5 mL). Aqueous Na₂CO₃/KOAc solution (1:1, 1.1 M, 1.5 mL)was added and the mixture was heated at 130° C. in a microwave for 40min. A further portion of Pd(dppf)₂Cl₂ (0.1 g, 0.12 mmol) was added andthe mixture was heated at 130° C. for a further 90 min. The solventswere removed under reduced pressure and the crude residue dissolved inEtOAc and water. The mixture was extracted with EtOAc and the combinedorganic layers passed through a phase separator cartridge. The solventwas removed under reduced pressure and the crude product was purifiedvia silica gel column chromatography (0-10% MeOH/DCM) to give1-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,2,3,6-tetrahydropyridineas a brown oil (44 mg, 16%). ¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H),5.89-5.86 (m, 1H), 3.82 (s, 3H), 3.19 (q, J=3.0 Hz, 2H), 2.74 (q, J=5.5Hz, 2H), 2.47-2.39 (m, 5H)

Step 2: Following the procedure for Example 230, starting with1-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,2,3,6-tetrahydropyridine(0.111 g, 0.5 mmol) gave 231 as a beige solid (75 mg, 35% over threesteps). ¹H NMR (400 MHz, CDCl₃) δ 8.35 (s, 1H), 7.63 (s, 1H), 7.37-7.24(m, 1H), 7.01 (t, J=8.5 Hz, 2H), 6.14 (s, 2H), 3.86 (s, 3H), 3.03-2.93(m, 2H), 2.73-2.62 (m, 1H), 2.30 (s, 3H), 2.15-1.97 (m, 4H), 1.86 (d,J=12.0 Hz, 2H). LCMS (ES+) m/z 433 (M+1)

Example 232(R)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(tetrahydrofuran-3-yloxy)-1H-pyrazol-4-yl)thiazole-4-carboxamide232 Step 1: (R)-1-Methyl-4-nitro-5-(tetrahydrofuran-3-yloxy)-1H-pyrazole

Following the procedure for Example 230 starting with5-chloro-1-methyl-4-nitro-1H-pyrazole and (R)-(−)-3-hydroxytetrahydrofuran gave(R)-1-methyl-4-nitro-5-(tetrahydrofuran-3-yloxy)-1H-pyrazole as a clearoil (90 mg, 34%). ¹H NMR (400 MHz, CDCl₃) δ 8.01 (s, 1H), 5.65 (q, J=3.4Hz, 1H), 4.10 (q, J=8.0 Hz, 1H), 4.02-3.87 (m, 2H), 3.81 (dd, J=11.3,3.4 Hz, 1H), 3.71 (s, 3H), 2.26 (td, J=7.3, 3.4 Hz, 2H)

Step 2: Following the procedure for Example 230, starting with(R)-1-methyl-4-nitro-5-(tetrahydrofuran-3-yloxy)-1H-pyrazole gave 232 asa white solid (70 mg, 38% over three steps). ¹H NMR (400 MHz, CDCl₃) δ8.26 (s, 1H), 7.60 (s, 1H), 7.37-7.28 (m, 1H), 7.08-6.98 (m, 2H), 6.15(s, 2H), 5.10-5.06 (m, 1H), 4.10-3.99 (m, 2H), 3.94-3.86 (m, 1H), 3.82(dd, J=10.8, 4.0 Hz, 1H), 3.68 (s, 3H), 2.28-2.09 (m, 2H). LCMS (ES+)m/z 422 (M+1)

Example 233(S)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(tetrahydrofuran-3-yloxy)-1H-pyrazol-4-yl)thiazole-4-carboxamide233 Step 1: (5)-1-Methyl-4-nitro-5-(tetrahydrofuran-3-yloxy)-1H-pyrazole

5-Chloro-1-methyl-4-nitro-1H-pyrazole and (S)-(+)-3-hydroxytetrahydrofuran gave(S)-1-methyl-4-nitro-5-(tetrahydrofuran-3-yloxy)-1H-pyrazole as a clearoil (52 mg, 20%). ¹H NMR (400 MHz, CDCl₃) δ 8.01 (s, 1H), 5.65 (q, J=3.4Hz, 1H), 4.10 (q, J=8.0 Hz, 1H), 4.02-3.87 (m, 2H), 3.84-3.76 (m, 1H),3.71 (s, 3H), 2.26 (td, J=7.3, 3.4 Hz, 2H)

Step 2: Following the procedure for Example 230, starting with(5)-1-methyl-4-nitro-5-(tetrahydrofuran-3-yloxy)-1H-pyrazole gave 233 asa white solid (60 mg, 59% over three steps). ¹H NMR (400 MHz, CDCl₃) δ8.26 (s, 1H), 7.60 (s, 1H), 7.37-7.28 (m, 1H), 7.08-6.98 (m, 2H), 6.15(s, 2H), 5.08 (dd, J=5.5, 4.0 Hz, 1H), 4.10-3.99 (m, 2H), 3.90 (td,J=8.5, 4.0 Hz, 1H), 3.82 (dd, J=11.0, 4.0 Hz, 1H), 3.68 (s, 3H),2.28-2.09 (m, 2H), 2.28-2.09. LCMS (ES+) m/z 422 (M+1)

Example 234(R)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-cyclopentyl-5-fluoropicolinamide234

Following procedures from Example 229, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16was converted to 234. ¹H NMR (400 MHz, DMSO) δ 9.54 (br, 1H), 8.00 (dd,J=8.4, 3.9 Hz, 1H), 7.88-7.80 (m, 1H), 7.71 (s, 1H), 3.68 (s, 3H),3.55-3.45 (m, 1H), 3.22-3.09 (m, 4H), 3.05-2095 (m, 1H), 2.12-1.45 (m,14H). MS (ESI) m/z: 401.2 [M+H⁺].

Example 235(R)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(5-(dimethylcarbamoyl)-2-fluorophenyl)-5-fluoropicolinamide235

Following procedures from Example 229, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16was converted to 235. ¹H NMR (400 MHz, DMSO) δ 8.24 (dd, J=8.6, 3.9 Hz,1H), 8.10 (t, J=9.1 Hz, 1H), 7.86 (dd, J=6.9, 1.9 Hz, 1H), 7.68 (dd,J=7.2, 4.2 Hz, 1H), 7.57 (s, 1H), 7.54-7.41 (m, 1H), 3.64 (s, 3H),3.19-3.04 (m, 4H), 2.99 (s, 6H), 2.93-2.84 (m, 1H), 1.82-1.64 (m, 3H),1.55-1.45 (m, 3H). MS (ESI) m/z: 498.2 [M+H⁺].

Example 236(R)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-cyclopentenyl-5-fluoropicolinamide236

Following procedures from Example 229, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16was converted to 236. ¹H NMR (400 MHz, DMSO) δ 9.55 (s, 1H), 8.01 (dd,J=8.5, 3.7 Hz, 1H), 7.91 (dd, J=11.2, 8.5 Hz, 1H), 7.68 (s, 1H), 6.80(s, 1H), 3.67 (s, 4H), 3.22-3.07 (m, 6H), 3.07-2.92 (m, 4H), 2.66 (d,J=7.0 Hz, 3H), 2.04-1.92 (m, 3H), 1.90-1.41 (m, 13H). MS (ESI) m/z:399.2 [M+H⁺].

Example 237(R)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)picolinamide237

Following procedures from Example 229, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16was converted to 237. ¹H NMR (400 MHz, DMSO) δ 9.11 (s, 1H), 8.46 (d,J=8.2 Hz, 1H), 8.28 (d, J=8.2 Hz, 1H), 7.54 (s, 1H), 3.65 (s, 3H),3.21-2.94 (m, 6H), 1.89-1.68 (m, 3H), 1.63-1.44 (m, 3H). MS (ESI) m/z:383.2 [M+H⁺].

Example 238(R)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide238

Following procedures from Example 229, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16was converted 238. ¹H NMR (400 MHz, DMSO) δ 8.30 (dd, J=8.7, 4.1 Hz,1H), 8.17 (t, J=8.9 Hz, 1H), 7.71 (dd, J=15.1, 8.3 Hz, 1H), 7.64 (d,J=14.2 Hz, 1H), 7.36 (t, J=8.2 Hz, 2H), 3.64 (s, 3H), 3.17-2.99 (m, 4H),2.94-2.82 (m, 1H), 1.80-1.60 (m, 3H), 1.59-1.33 (m, 3H). MS (ESI) m/z:445.2 [M+H⁺].

Example 2395-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-morpholino-1H-pyrazol-4-yl)thiazole-4-carboxamide239 Step 1: 4-(1-Methyl-4-nitro-1H-pyrazol-5-yl)morpholine

5-Chloro-1-methyl-4-nitro-1H-pyrazole and morpholine gave4-(1-methyl-4-nitro-1H-pyrazol-5-yl)morpholine as a pale yellow solid(200 mg, 78%). ¹H NMR (400 MHz, CDCl₃) δ 8.04 (s, 1H), 3.86 (t, J=4.6Hz, 4H), 3.81 (s, 3H), 3.23 (t, J=4.6 Hz, 4H)

Step 2: Following the procedure for Example 230, starting with4-(1-methyl-4-nitro-1H-pyrazol-5-yl)morpholine gave 239 as a dark creamsolid (76 mg, 38% over three steps). ¹H NMR (400 MHz, CDCl₃) δ 8.47 (s,1H), 7.72 (s, 1H), 7.38-7.24 (m, 1H), 7.03 (t, J=8.8 Hz, 2H), 6.13 (s,2H), 3.83 (t, J=4.3 Hz, 4H), 3.77 (s, 3H), 3.16 (t, J=4.3 Hz, 4H). LCMS(ES+) m/z 421 (M+1)

Example 240(R)-5-amino-2-(2,6-difluorophenyl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide240 Step 1: (R)-1-(1-Methyl-4-nitro-1H-pyrazol-5-yl)pyrrolidin-3-ol

5-Chloro-1-methyl-4-nitro-1H-pyrazole and (R)-(+)-3-hydroxypyrrolidinegave (R)-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyrrolidin-3-ol as a yellowsolid (264 mg, 100%). ¹H NMR (400 MHz, CDCl₃) δ 8.05 (s, 1H), 4.64-4.59(m, 1H), 3.78 (s, 3H), 3.71-3.59 (m, 2H), 3.39 (td, J=8.8, 3.4 Hz, 1H),3.24 (dt, J=10.2, 1.6 Hz, 1H), 2.34-2.23 (m, 1H), 2.15-2.03 (m, 2H)

Step 2: Following the procedure for Example 230, starting with(R)-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyrrolidin-3-ol gave 240 as anoff-white foam (48 mg, 20% over three steps). ¹H NMR (400 MHz, CDCl₃) δ9.55 (s, 1H), 7.91 (s, 1H), 7.36-7.30 (m, 1H), 7.07-7.00 (m, 2H), 6.23(s, 2H), 4.51 (s, 1H), 3.75 (s, 3H), 3.49-3.28 (m, 4H), 3.26-3.22 (m,1H), 2.09-2.07 (m, 2H). LCMS (ES+) m/z 421 (M+1)

Example 2415-amino-N-(5-(4-aminoazepan-1-yl)-1-ethyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide241

A solution of tert-butyl2-(2,6-difluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate(0.17 g, 0.26 mmol) in HCl in 1,4-dioxane (4 M, 5 mL) was allowed tostand at room temperature for 40 hr. The reaction mixture wasconcentrated under reduced pressure and the residue dissolved in 50%aqueous MeOH (20 mL). K₂CO₃ (1.22 g, 8.84 mmol) was added and themixture heated at 60° C. for 3 hr. The mixture was allowed to cool,concentrated to approximately 5 mL and extracted with DCM. The combinedorganic layers were passed through a phase separation cartridge and thesolvent removed under reduced pressure. Purification of the residue bypassing through an SCX column washing with DCM and MeOH and eluting with1 N ammonia in MeOH gave 241 as a cream solid (118 mg, 99%). ¹H-NMR (400MHz, CDCl₃) δ 8.67 (s, 1H), 7.92 (s, 1H), 7.36-7.28 (m, 1H), 7.06-6.97(m, 2H), 6.14 (s, 2H), 4.05 (q, J=7 Hz, 2H), 3.29-3.12 (m, 5H),2.02-1.88 (m, 3H), 1.75-1.60 (m, 3H), 1.43 (t, J=7 Hz, 3H). RNH₂ notseen. LCMS (ES+) m/z 462.0 (M+1).

Example 242(S)-5-amino-2-(2,6-difluorophenyl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide242 Step 1: (S)-1-(1-Methyl-4-nitro-1H-pyrazol-5-yl)pyrrolidin-3-ol

Following Example 231, 5-Chloro-1-methyl-4-nitro-1H-pyrazole and(S)-(−)-3-hydroxypyrrolidine gave(S)-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyrrolidin-3-ol (250 mg, 96%).¹H NMR (400 MHz, CDCl₃) δ 8.05 (s, 1H), 4.64-4.59 (m, 1H), 3.78 (s, 3H),3.71-3.59 (m, 2H), 3.39 (td, J=8.8, 3.4 Hz, 1H), 3.24 (dt, J=10.2, 1.6Hz, 1H), 2.34-2.23 (m, 1H), 2.14-2.04 (m, 2H)

Step 2: Following the procedure for Example 230, starting with(S)-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyrrolidin-3-ol gave 242 as aoff-white solid (20 mg, 16% over three steps). ¹H NMR (400 MHz, CDCl₃) δ9.55 (s, 1H), 7.91 (s, 1H), 7.36-7.31 (m, 1H), 7.05 (t, J=8.8 Hz, 2H),6.23 (s, 2H), 4.51 (s, 1H), 3.75 (s, 3H), 3.50-3.20 (m, 5H), 2.09-2.07(m, 2H). LCMS (ES+) m/z 421 (M+1)

Example 2435-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide243 Step 1: 5-(3,6-Dihydro-2H-pyran-4-yl)-1-methyl-4-nitro-1H-pyrazole

Following Example 231, reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazoleand 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester gave5-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-4-nitro-1H-pyrazole (167 mg,65%). ¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H), 5.99-5.94 (m, 1H), 4.37(q, J=2.8 Hz, 2H), 3.99 (t, J=5.3 Hz, 2H), 3.84 (s, 3H), 2.40-2.35 (m,2H)

Step 2: A solution of5-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-4-nitro-1H-pyrazole (80 mg, 0.38mmol) in MeOH (20 mL) was passed through the H-Cube® (30 bar, 25° C.,flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removedunder reduced pressure to afford crude1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine as a lightyellow oil (64 mg, 0.35 mmol). To a solution of this amine (60 mg, 0.33mmol) in DCM (20 mL) was added DIPEA (0.5 mL, 2.87 mmol), PyBOP (0.34 g,0.66 mmol) and5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid (124 mg, 0.35 mmol) and the mixture was stirred at room temperaturefor 18 hr. The mixture was diluted with DCM and washed with water. Theorganic layer was separated, dried over MgSO₄ and the solvent removedunder reduced pressure. Purification via silica gel columnchromatography (0-80% EtOAc/isohexane) gave tert-butyl2-(2,6-difluorophenyl)-4-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateas an off-white solid (102 mg, 59%). This solid (100 mg, 0.19 mmol) wasstirred in HCl in 1,4-dioxane (4.0 M, 1.9 mL) at room temperature for 18hr. The solvents were removed under reduced pressure and the cruderesidue was re-dissolved in MeOH and loaded onto an SCX column. Thecolumn was washed with MeOH and 7 N ammonia in MeOH to yield 301 as apeach solid (59 mg, 73%). ¹H NMR (400 MHz, CDCl₃) δ 8.42 (s, 1H), 7.69(s, 1H), 7.34-7.29 (m, 1H), 7.02 (t, J=8.7 Hz, 2H), 6.11 (s, 2H), 4.09(dd, J=11.6, 4.2 Hz, 2H), 3.88 (s, 3H), 3.50 (t, J=11.6 Hz, 2H),3.02-2.95 (m, 1H), 2.17-2.08 (m, 2H), 1.78 (d, J=13.4 Hz, 2H). LCMS(ES+) m/z 420 (M+1)

Example 2445-amino-N-(1-methyl-1H-pyrazol-4-yl)-2-(3-morpholinophenyl)thiazole-4-carboxamide244

Following Example 278, Suzuki coupling of (tert-butyl2-bromo-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate and3-morpholinophenylboronic acid gave 244 as a beige solid (56 mg, 59%over two steps). ¹H NMR (400 MHz, CDCl₃) δ 8.65 (s, 1H), 7.96 (s, 1H),7.53 (s, 1H), 7.25-6.95 (m, 4H), 6.07 (s, 2H), 3.92-3.88 (m, 7H), 3.24(t, J=5 Hz, 4H). LCMS (ES+) m/z 385 (M+1)

Example 2455-amino-2-(2,6-difluorophenyl)-N-(5-(4-fluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide245 Step 1: 4-Fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine

Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 4-fluoropiperidinehydrochloride gave4-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine as a white solid(280 mg, 99%). ¹H NMR (400 MHz, CDCl₃) δ 8.02 (s, 1H), 4.86 (dtt,J=47.9, 7.1, 3.6 Hz, 1H), 3.77 (s, 3H), 3.37 (d, J=9.4 Hz, 2H),3.20-3.12 (m, 2H), 2.16-2.06 (m, 1H), 2.07-1.92 (m, 3H)

Step 2: Following the procedure for Example 243 starting with4-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine gave 245 as abrown foam (146 mg, 59% over three steps). ¹H NMR (400 MHz, CDCl₃) δ8.50 (s, 1H), 7.74 (s, 1H), 7.32 (tt, J=8.5, 6.0 Hz, 1H), 7.06-7.00 (m,2H), 6.12 (s, 2H), 4.88-4.71 (m, 1H), 3.75 (s, 2H), 3.33 (s, 3H),3.11-3.03 (m, 2H), 2.11-1.94 (m, 4H). LCMS (ES+) m/z 437 (M+1)

Example 2465-amino-2-(2,6-difluorophenyl)-N-(5-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide246 Step 1: 4,4-Difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine

Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 4,4di-fluoropiperidine hydrochloride gave4,4-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine as a whitesolid (289 mg, 97%). ¹H NMR (400 MHz, CDCl₃) δ 8.03 (s, 1H), 3.79 (s,3H), 3.36-3.31 (m, 4H), 2.22-2.09 (m, 4H)

Step 2: Following the procedure for Example 243 starting with4,4-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine gave 246 asa yellow foam (130 mg, 57% over three steps). ¹H NMR (400 MHz, CDCl₃) δ8.50 (s, 1H), 7.75 (s, 1H), 7.32 (tt, J=8.5, 6.0 Hz, 1H), 7.08-6.99 (m,2H), 6.11 (s, 2H), 3.76 (s, 3H), 3.27 (t, J=5.5 Hz, 4H), 2.20-2.07 (m,4H). LCMS (ES+) m/z 455 (M+1)

Example 247(S)-5-amino-2-(2,6-difluorophenyl)-N-(5-(3-fluoropyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide247 Step 1: (5)-5-(3-Fluoropyrrolidin-1-yl)-1-methyl-4-nitro-1H-pyrazole

Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and(S)-3-fluoropyrrolidine gave(S)-5-(3-fluoropyrrolidin-1-yl)-1-methyl-4-nitro-1H-pyrazole as a yellowsolid (220 g, 83%). ¹H NMR (400 MHz, CDCl₃) δ 8.05 (s, 1H), 5.48-5.31(m, 1H), 3.79 (s, 3H), 3.73-3.57 (m, 2H), 3.49-3.37 (m, 2H), 2.46-2.27(m, 2H)

Step 2: Following the procedure for Example 243 starting with(S)-5-(3-fluoropyrrolidin-1-yl)-1-methyl-4-nitro-1H-pyrazole gave 247 asa light brown foam (35 mg, 18% over three steps). ¹H NMR (400 MHz,CDCl₃) δ 8.39 (s, 1H), 7.73 (s, 1H), 7.36-7.27 (m, 1H), 7.07-6.97 (m,2H), 6.13 (s, 2H), 5.37-5.19 (m, 1H), 3.75 (s, 3H), 3.64-3.43 (m, 3H),3.38-3.31 (m, 1H), 2.34-2.13 (m, 2H). LCMS (ES+) m/z 423 (M+1)

Example 248(R)-5-amino-2-(2,6-difluorophenyl)-N-(5-(3-fluoropyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide248 Step 1: (R)-5-(3-Fluoropyrrolidin-1-yl)-1-methyl-4-nitro-1H-pyrazole

Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and(R)-3-fluoropyrrolidine gave(R)-5-(3-fluoropyrrolidin-1-yl)-1-methyl-4-nitro-1H-pyrazole as a yellowsolid (153 mg, 58%). ¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 1H), 5.48-5.31(m, 1H), 3.79 (s, 3H), 3.73-3.57 (m, 2H), 3.48-3.37 (m, 2H), 2.46-2.27(m, 2H)

Step 2: Following the procedure for Example 243 starting with(R)-5-(3-fluoropyrrolidin-1-yl)-1-methyl-4-nitro-1H-pyrazole gave 248 aslight brown solid (50 mg, 29% over three steps). ¹H NMR (400 MHz, CDCl₃)δ 8.39 (s, 1H), 7.73 (s, 1H), 7.36-7.28 (m, 1H), 7.06-6.96 (m, 2H), 6.14(s, 2H), 5.41-5.21 (m, 1H), 3.75 (s, 3H), 3.64-3.43 (m, 3H), 3.38-3.31(m, 1H), 2.34-2.14 (m, 2H). LCMS (ES+) m/z 423 (M+1)

Example 2495-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(piperidin-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide249 Step 1: 1-(1-Methyl-4-nitro-1H-pyrazol-5-yl)piperidine

Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and piperidine gave1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine as a white solid (232 mg,89%). ¹H NMR (400 MHz, CDCl₃) δ 8.00 (s, 1H), 3.74 (s, 3H), 3.18-3.12(m, 4H), 1.74-1.63 (m, 6H)

Step 2: Following the procedure for Example 243 starting with1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine gave 249 as a light brownfoam (129 mg, 50% over three steps). ¹H NMR (400 MHz, CDCl₃) δ 8.56 (s,1H), 7.77 (s, 1H), 7.36-7.27 (m, 1H), 7.08-6.98 (m, 2H), 6.13 (s, 2H),3.72 (s, 3H), 3.09 (t, J=5.0 Hz, 4H), 1.73-1.65 (m, 4H), 1.62-1.55 (m,2H). LCMS (ES+) m/z 419 (M+1)

Example 2505-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-cyanophenyl)thiazole-4-carboxamide250

Following Example 278, Suzuki coupling of tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateand 3-cyanophenyl boronic acid gave 250 as a pale brown solid (36 mg,42% over two steps). ¹H NMR (400 MHz, d₆-DMSO) δ 9.09 (s, 1H), 8.42 (s,1H), 8.11 (d, J=7.9 Hz, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.68 (t, J=7.9 Hz,1H), 7.56 (s, 2H), 7.33 (s, 1H), 3.66 (s, 3H), 3.16-2.99 (m, 4H), 2.47(d, J=5.7 Hz, 2H), 1.82-1.73 (m, 4H), 1.30-1.17 (m, 3H). LCMS (ES+) m/z437 (M+1)

Example 2515-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-fluorophenyl)thiazole-4-carboxamide251

Following Example 278, Suzuki coupling of tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateand 3-phenylboronic acid gave 251 as a brown solid (22 mg, 25% over twosteps). ¹H NMR (400 MHz, d₆-DMSO) δ 9.00 (s, 1H), 7.79 (dt, J=10.3, 2.0Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.56-7.48 (m, 3H), 7.36 (s, 1H), 7.26(td, J=8.5, 2.6 Hz, 1H), 3.66 (s, 3H), 3.15-3.00 (m, 4H), 2.48 (d, J=5.7Hz, 2H), 1.78 (d, J=11.9 Hz, 4H), 1.30-1.20 (m, 3H). LCMS (ES+) m/z 430(M+1)

Example 2525-amino-N-(5-(3-(2-aminoethyl)pyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide252

tert-Butyl2-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-yl)ethylcarbamatewas prepared according to Example 2. Using this amine, 252 was preparedaccording to Example 140. ¹H NMR (400 MHz, DMSO) δ 8.64 (br, 1H),7.61-7.38 (m, 4H), 7.26 (t, J=8.7 Hz, 2H), 3.62 (s, 3H), 2.87 (t, J=8.3Hz, 1H), 2.38-2.17 (m, 2H), 2.09-1.97 (m, 1H), 1.56-1.42 (m, 3H). MS(ESI) m/z: 448.2 [M+H⁺].

Example 253(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-5-(trifluoromethyl)phenyl)thiazole-4-carboxamide253

Following procedures from Example 141, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16was converted to 253. ¹H NMR (400 MHz, DMSO) δ 9.10 (br, 1H), 8.63 (d,J=6.7 Hz, 1H), 7.86-7.74 (m, 1H), 7.66-7.56 (m, 1H), 7.51 (br, 2H), 7.44(s, 1H), 3.65 (s, 3H), 3.23-3.04 (m, 4H), 3.00-2.93 (m, 1H), 1.86-1.75(m, 3H), 1.67-1.42 (m, 3H). MS (ESI) m/z: 498.2 [M+H⁺].

Example 254N-(5-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-1-methyl-1H-pyrazol-4-yl)-5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxamide254

5-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-1-methyl-1H-pyrazol-4-aminewas prepared according to Example 2. Using this amine, 254 was preparedaccording to Example 140. ¹H NMR (400 MHz, DMSO) δ 9.70 (s, 1H), 7.56(d, J=14.8 Hz, 1H), 7.54-7.40 (m, 3H), 7.32-7.18 (m, 2H), 3.86 (s, 1H),3.62 (s, 3H), 3.30-3.20 (m, 3H), 2.87 (d, J=9.6 Hz, 1H), 2.78 (d, J=8.5Hz, 1H), 1.91 (d, J=9.4 Hz, 1H), 1.64 (d, J=9.4 Hz, 1H). MS (ESI) m/z:432.1 [M+H⁺].

Example 2555-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide255 Step 1: tert-Butyl2-(2,6-difluorophenyl)-4-(1-methyl-5-(tert-butyloxycarbonylpyrrolidin-3-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

5-Chloro-1-methyl-4-nitro-1H-pyrazole (0.2 g, 1.24 mmol), tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate(0.437 g, 1.48 mmol) and aqueous Na₂CO₃/KOAc solution (1:1, 1.1 M, 1.5mL) were suspended in MeCN (5 mL). The mixture was degassed under astream of nitrogen for 5 min. Pd(dppf)₂Cl₂ (0.1 g, 0.123 mmol) was addedand the mixture was heated at 130° C. in a microwave for 90 min. Afurther portion of Pd(dppf)₂Cl₂ (50 mg, 0.06 mmol) was added and themixture was heated at 130° C. for a further 90 min. The solvents wereremoved under reduced pressure and the crude residue partitioned betweenEtOAc and water. The organic layer was separated, dried over MgSO₄ andconcentrated under reduced pressure. The crude product was purified viasilica gel column chromatography (40-60% EtOAc/isohexane) to give theintermediate nitro-pyrazole as a yellow oil (76 mg, 21%). A solution ofthis oil (70 mg, 0.23 mmol) in MeOH (20 mL) was passed through theH-Cube® (50 bar, 20° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge).The solvent was removed under reduced pressure to afford tert-butyl3-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyrrolidine-1-carboxylate as ayellow viscous oil (55 mg, 87%). To a solution of this oil (55 mg, 0.21mmol) in DCM (20 mL) and DIPEA (0.5 mL) was added PyBOP (161 mg, 0.31mmol) and5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid (77 mg, 0.22 mmol) and the mixture was stirred at room temperaturefor 18 hr. The mixture was diluted with DCM and washed with water. Theorganic layer was separated, dried over MgSO₄ and the solvent removedunder reduced pressure. Purification via silica gel columnchromatography (75% EtOAc/isohexane) gave tert-butyl2-(2,6-difluorophenyl)-4-(1-methyl-5-(tert-butyloxycarbonylpyrrolidin-3-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateas a pale yellow glass (44 mg, 35%). ¹H NMR (400 MHz, CDCl₃) δ 10.32 (s,1H), 8.70-8.50 (m, 2H), 7.80.7.70 (m, 1H), 7.89-7.82 (m, 1H), 7.05 (t,J=8.7 Hz, 2H), 3.89 (s, 3H), 3.85-3.32 (m, 5H), 2.43-2.25 (m, 2H), 1.54(s, 18H)

Step 2: Acidic deprotection of the two Boc groups of tert-butyl2-(2,6-difluorophenyl)-4-(1-methyl-5-(tert-butyloxycarbonylpyrrolidin-3-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamategave 255 as a peach foam (19 mg, 65%). ¹H NMR (400 MHz, CDCl₃) δ 11.79(s, 1H), 8.18 (s, 1H), 7.34-7.28 (m, 1H), 7.05-6.98 (m, 2H), 6.24 (s,2H), 3.84 (s, 3H), 3.49-3.44 (m, 1H), 3.38-3.32 (m, 2H), 3.07 (dd,J=9.5, 6.5 Hz, 1H), 2.96-2.91 (m, 1H), 2.27-2.22 (m, 1H), 1.90-1.82 (m,1H). Alkyl NH not seen. LCMS (ES+) m/z 405 (M+1)

Example 2565-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cyclopentenylthiazole-4-carboxamide256

Following Example 278, Suzuki coupling of tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateand cyclopent-1-ene-1-boronic acid gave 256 as an off-white solid (23mg, 29% over two steps). ¹H NMR (400 MHz, d₆-DMSO) δ 8.60 (s, 1H), 7.46(s, 1H), 7.36 (s, 2H), 6.21 (t, J=2.4 Hz, 1H), 3.66 (s, 3H), 3.12-2.97(m, 4H), 2.75 (t, J=7.3 Hz, 2H), 2.54 (s, 2H), 2.48 (d, J=5.9 Hz, 2H),2.03-1.93 (m, 2H), 1.84-1.74 (m, 4H), 1.33-1.16 (m, 3H). LCMS (ES+) m/z402 (M+1)

Example 257(E)-5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-cyclohexylvinyl)thiazole-4-carboxamide257

Following Example 278, Suzuki coupling of tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateand trans-(2-cyclohexylvinyl)boronic acid gave 257 as an off-white solid(17 mg, 20% over two steps). ¹H NMR (400 MHz, d₆-DMSO) δ 8.70 (s, 1H),7.36 (s, 2H), 7.31 (s, 1H), 6.40 (dd, J=16.0, 1.3 Hz, 1H), 6.20 (dd,J=16.0, 6.7 Hz, 1H), 3.63 (s, 3H), 3.10-2.96 (m, 6H), 2.47 (d, J=5.9 Hz,2H), 2.21-2.10 (m, 1H), 1.83-1.71 (m, 7H), 1.35-1.13 (m, 8H). LCMS (ES+)m/z 444 (M+1)

Example 2585-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide258 Step 1: tert-Butyl4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate

Following Example 231, reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazoleand tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylategave tert-butyl4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate(310 mg, 80%). ¹H NMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 5.89 (s br, 1H),4.14 (s br, 2H), 3.81 (s, 3H), 3.73-3.67 (m, 2H), 2.37 (s br, 2H), 1.27(s) and 1.24 (s) (9H)

Step 2: tert-butyl4-(4-amino-1-methyl-1H-pyrazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate

To a solution of tert-butyl4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate(0.15 g, 0.48 mmol) in ethanol (10 mL) and water (1 mL) was addedammonium chloride (0.131 g, 2.44 mmol) and iron powder (0.109 g, 1.95mmol). The mixture was heated at 100° C. for 1 hr. The mixture wascooled and filtered through celite and washed with EtOAc. The organiclayer was washed with water, separated and dried over MgSO₄. The solventwas removed under reduced pressure to yield tert-butyl4-(4-amino-1-methyl-1H-pyrazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylateas a brown oil (86 mg, 64%).

Step 3: tert-butyl2-(2,6-difluorophenyl)-4-(1-methyl-5-(tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

To a solution of tert-butyl4-(4-amino-1-methyl-1H-pyrazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate(85 mg, 0.31 mmol) in DCM (20 mL) was added DIPEA (0.5 mL, 2.87 mmol),PyBOP (0.238 g, 0.46 mmol) and5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid (0.114 g, 0.32 mmol) and the mixture was stirred at roomtemperature for 18 hr. The mixture was diluted with DCM and washed withwater. The organic layer was separated, dried over MgSO₄ and the solventremoved under reduced pressure. Purification via silica gel columnchromatography (0-75% EtOAc/isohexane) gave tert-butyl2-(2,6-difluorophenyl)-4-(1-methyl-5-(tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateas a white solid (54 mg, 29%).

Step 4: tert-butyl2-(2,6-difluorophenyl)-4-(1-methyl-5-(tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate(0.10 g, 0.16 mmol) was dissolved in MeOH (3 mL) and HCl in 1,4-dioxane(4.0 M, 3 mL) was added. The mixture was stirred at room temperature for18 hr. The solvents were removed under reduced pressure and the cruderesidue was re-dissolved in MeOH and loaded onto an SCX column. Thecolumn was washed with MeOH and eluted with 7 N ammonia in MeOH to give258 as a yellow solid (64 mg, 95%). ¹H NMR (400 MHz, CDCl₃) δ 8.69 (s,1H), 8.06 (s, 1H), 7.36-7.29 (m, 1H), 7.02 (t, J=8.9 Hz, 2H), 6.12 (s,2H), 6.01 (s, 1H), 3.82 (s, 3H), 3.61 (d, J=3.4 Hz, 2H), 3.14 (t, J=5.5Hz, 2H), 2.34 (s, 3H). LCMS (ES+) m/z 417 (M+1)

Example 2595-amino-2-(2,6-difluorophenyl)-N-(5-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide259 Step 1:(3S,4S)-1-(1-Methyl-4-nitro-1H-pyrazol-5-yl)pyrrolidine-3,4-diol

Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and(3S,4S)-pyrrolidine-3,4-diol gave(3S,4S)-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyrrolidine-3,4-diol as abright yellow solid (258 mg, 91%). ¹H NMR (400 MHz, d₄-MeOD) δ 8.04 (s,1H), 4.27-4.22 (m, 2H), 3.98 (dd, J=10.0, 4.4 Hz, 2H), 3.84 (s, 3H),3.31-3.25 (m, 2H)

Step 2: Following the procedure for Example 243 starting with(3S,4S)-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyrrolidine-3,4-diol gave259 as a yellow solid (27 mg, 5% over three steps). ¹H NMR (400 MHz,CDCl₃) δ 9.45 (s, 1H), 7.85 (s, 1H), 7.39-7.30 (m, 1H), 7.11-6.99 (m,2H), 6.22 (s, 2H), 4.30 (d, J=3.5 Hz, 2H), 3.76 (s, 3H), 3.69 (dd,J=11.5, 3.5 Hz, 2H), 3.28 (d, J=11.5 Hz, 2H), 2.76 (s, 2H). LCMS (ES+)m/z 437 (M+1)

Example 2605-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-((tetrahydro-2H-pyran-4-yl)methylamino)-1H-pyrazol-4-yl)thiazole-4-carboxamide260 Step 1:1-Methyl-4-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-5-amine

Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and(tetrahydro-2H-pyran-4-yl)methanamine gave1-methyl-4-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-5-amineas an off-white solid (277 mg, 93%). ¹H NMR (400 MHz, CDCl₃) δ 7.88 (d,J=1.6 Hz, 1H), 6.75 (s, 1H), 4.01 (dd, J=11.6, 4.3 Hz, 2H), 3.85 (d,J=1.0 Hz, 3H), 3.44-3.32 (m, 4H), 1.90-1.76 (m, 1H), 1.75-1.68 (m, 2H),1.38 (qd, J=12.4, 4.4 Hz, 2H)

Step 2: Following the procedure for Example 243 starting with1-methyl-4-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-5-aminegave 260 as a yellow solid (99 mg, 19% over three steps). ¹H NMR (400MHz, d₆-DMSO) δ 8.84 (s, 1H), 7.64-7.49 (m, 3H), 7.45 (s, 1H), 7.30 (t,J=8.5 Hz, 2H), 4.90 (t, J=6.5 Hz, 1H), 3.76 (dd, J=11.5, 4.0 Hz, 2H),3.62 (s, 3H), 3.17 (t, J=11.5 Hz, 2H), 2.82 (t, J=6.5 Hz, 2H), 1.69-1.55(m, 3H), 1.20-1.08 (m, 2H). LCMS (ES+) m/z 449 (M+1)

Example 2615-amino-2-(2,6-difluorophenyl)-N-(5-(dimethylamino)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide261 Step 1: N,N,1-Trimethyl-4-nitro-1H-pyrazol-5-amine

Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and dimethylamine gaveN,N,1-trimethyl-4-nitro-1H-pyrazol-5-amine as a yellow solid (210 g,100%). ¹H NMR (400 MHz, CDCl₃) δ 8.01 (s, 1H), 3.75 (s, 3H), 2.90 (s,6H)

Step 2: Following the procedure for Example 243 starting withN,N,1-trimethyl-4-nitro-1H-pyrazol-5-amine gave 261 as a light brownsolid (0.26 g, 54% over three steps). ¹H NMR (400 MHz, CDCl₃) δ 8.48 (s,1H), 7.75 (s, 1H), 7.39-7.29 (m, 1H), 7.09-6.99 (m, 2H), 6.18 (s, 2H),3.75 (s, 3H), 2.87 (s, 6H). LCMS (ES+) m/z 379 (M+1)

Example 2625-amino-N-(5-(cyclohexyloxy)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide262 Step 1: 5-(Cyclohexyloxy)-1-methyl-4-nitro-1H-pyrazole

Following the procedure for Example 230 reaction of5-chloro-1-methyl-4-nitro-1H-pyrazole and cyclohexanol gave5-(cyclohexyloxy)-1-methyl-4-nitro-1H-pyrazole as off-white solid (132mg, 47%). ¹H NMR (400 MHz, CDCl₃) δ 7.99 (s, 1H), 4.76-4.67 (m, 1H),3.70 (s, 3H), 2.10-2.02 (m, 2H), 1.85-1.78 (m, 2H), 1.64-1.52 (m, 2H),1.43-1.22 (m, 3H), 0.96-0.81 (m, 1H)

Step 2: Following the procedure for Example 243 starting with5-(cyclohexyloxy)-1-methyl-4-nitro-1H-pyrazole gave 262 as a light brownsolid (157 mg, 41% over three steps). ¹H NMR (400 MHz, CDCl₃) δ 8.39 (s,1H), 7.80 (s, 1H), 7.38-7.29 (m, 1H), 7.09-6.99 (m, 2H), 6.18 (s, 2H),4.21-4.12 (m, 1H), 3.71 (s, 3H), 2.09-1.98 (m, 3H), 1.86-1.78 (m, 2H),1.66-1.50 (m, 3H), 1.39-1.25 (m, 2H). LCMS (ES+) m/z 434 (M+1)

Example 2635-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(piperidin-4-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide263

Following the procedure for Example 243 starting with tert-butyl4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylategave 263 as an orange solid (28 mg, 18% over three steps). ¹H NMR (400MHz, d₆-DMSO) δ 8.77 (s, 1H), 7.61-7.48 (m, 3H), 7.46 (s, 1H), 7.30 (t,J=8.8 Hz, 2H), 3.80 (s, 3H), 3.09 (d, J=12.3 Hz, 2H), 2.97-2.87 (m, 1H),2.66 (t, J=12.3 Hz, 2H), 1.92-1.68 (m, 4H). Alkyl NH not seen. LCMS(ES+) m/z 419 (M+1). LCMS (ES+) m/z 488 (M+1)

Example 2645-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide264 Step 1: tert-Butyl(1-(1-(cyclopropylmethyl)-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate

Reaction of 5-chloro-1-cyclopropylmethyl-4-nitro-1H-pyrazole andtert-butyl piperidin-4-ylmethylcarbamate gave tert-butyl(1-(1-(cyclopropylmethyl)-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamateas a pale yellow gum (0.57 g, 95%). ¹H NMR (400 MHz, CDCl₃) δ 8.07-8.03(m, 1H), 4.63 (s, 1H), 3.91 (d, J=7.1 Hz, 2H), 3.40-3.32 (m, 2H),3.13-3.06 (m, 2H), 2.95 (d, J=11.5 Hz, 2H), 1.81 (d, J=12.9 Hz, 2H),1.46 (s, 9H), 1.42-1.14 (m, 3H), 0.95-0.82 (m, 1H), 0.63-0.57 (m, 2H),0.42-0.35 (m, 2H)

Step 2: Following the procedures of Example 230, tert-butyl(1-(1-(cyclopropylmethyl)-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamatewas converted to 264 as a cream solid (125 mg, 53% over three steps). ¹HNMR (400 MHz, d₆-DMSO) δ 8.75 (s, 1H), 7.62-7.52 (m, 4H), 7.36-7.28 (m,2H), 3.83 (d, J=6.8 Hz, 2H), 3.07 (d, J=7.8 Hz, 4H), 2.60 (d, J=6.8 Hz,2H), 1.80 (d, J=12.4 Hz, 2H), 1.50-1.40 (m, 1H), 1.30-1.20 (m, 3H),0.55-0.48 (m, 2H), 0.40-0.34 (m, 2H). Alkyl NH₂ not seen. LCMS (ES+) m/z488 (M+1) Example 2655-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cyclohexenylthiazole-4-carboxamide265

Following Example 278, Suzuki coupling of tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateand cyclohex-1-ene-1-boronic acid gave 265 as a pale brown solid (21 mg,26% over two steps). ¹H NMR (400 MHz, d₆-DMSO) δ 8.61 (s, 1H), 7.43 (s,1H), 7.26 (s, 2H), 6.25 (s br, 1H), 3.64 (s, 3H), 3.07-2.94 (m, 4H),2.47 (d, J=6.1 Hz, 4H), 2.19 (s, 2H), 1.77 (d, J=12.2 Hz, 2H), 1.73-1.58(m, 4H), 1.34-1.14 (m, 3H). Alkyl NH₂ not seen. LCMS (ES+) m/z 416 (M+1)

Example 266(E)-5-Amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cycloheptenylthiazole-4-carboxamide266

Following the procedure for Example 337 starting with tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateand 1-cycloheptenylboronic acid pinacol ester gave 266 as a pale brownsolid (25 mg, 28%). ¹H NMR (400 MHz, d₆-DMSO) δ 8.64 (s, 1H), 7.43 (s,1H), 7.29 (s, 2H), 6.38 (t, J=6.7 Hz, 1H), 3.64 (s, 3H), 3.08-2.94 (m,4H), 2.78 (d, J=8.2 Hz, 2H), 2.47 (d, J=6.2 Hz, 2H), 2.35-2.20 (m, 2H),1.82-1.72 (m, 4H), 1.56-1.49 (m, 4H), 1.33-1.11 (m, 3H). LCMS (ES+) m/z430 (M+1).

Example 2675-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-ethylphenyl)thiazole-4-carboxamide267

Following Example 278, Suzuki coupling of tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateand 3-ethylphenyl boronic acid gave 267 as an off-white solid (25 mg,29% over two steps). ¹H NMR (400 MHz, d₆-DMSO) δ 8.89 (s, 1H), 7.71 (s,1H), 7.61 (d, J=7.8 Hz, 1H), 7.43-7.33 (m, 4H), 7.26 (d, J=7.8 Hz, 1H),3.64 (s, 3H), 3.14-2.98 (m, 4H), 2.67 (q, J=7.6 Hz, 2H), 2.46 (d, J=5.7Hz, 2H), 1.77 (d, J=11.7 Hz, 2H), 1.32-1.19 (m, 6H). Alkyl NH₂ not seen.LCMS (ES+) m/z 440 (M+1)

Example 2685-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-methoxyphenyl)thiazole-4-carboxamide268

Following Example 278, Suzuki coupling of tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateand 3-methoxyphenyl boronic acid gave 268 as a brown solid (153 mg, 17%over two steps). ¹H NMR (400 MHz, d₆-DMSO) δ 8.92 (s, 1H), 7.47-7.29 (m,6H), 6.98 (d, J=7.7 Hz, 1H), 3.84 (s, 3H), 3.64 (s, 3H), 3.12-2.95 (m,4H), 2.47 (d, J=6.0 Hz, 2H), 1.76 (d, J=11.7 Hz, 2H), 1.30-1.17 (m, 3H).Alkyl NH₂ not seen. LCMS (ES+) m/z 442 (M+1)

Example 2695-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-isopropylphenyl)thiazole-4-carboxamide269

Following Example 278, Suzuki coupling of tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateand 3-isopropylbenzene boronic acid gave 269 as a red gum (38 mg, 41%over two steps). ¹H NMR (400 MHz, d₆-DMSO) δ 8.55 (s, 1H), 7.54-7.33 (m,6H), 7.28 (t, J=7.5 Hz, 1H), 3.71 (t, J=9.2 Hz, 1H), 3.62 (s, 3H),3.11-2.93 (m, 4H), 2.42 (d, J=5.4 Hz, 2H), 1.73 (d, J=11.3 Hz, 2H),1.27-1.21 (m, 9H). Alkyl NH₂ not seen. LCMS (ES+) m/z 454 (M+1)

Example 2705-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-isopropyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide270 Step 1: tert-Butyl(1-(1-isopropyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate

Reaction of 5-chloro-1-isopropyl-4-nitro-1H-pyrazole and tert-butylpiperidin-4-ylmethylcarbamate gave tert-butyl(1-(1-isopropyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamateas a pale yellow solid (0.45 g, 92%). ¹H NMR (400 MHz, CDCl₃) δ 8.06 (s,1H), 4.78 (hep, J=6.7 Hz, 1H), 4.64 (s, 1H), 3.42-3.29 (m, 2H), 3.11 (t,J=6.6 Hz, 2H), 2.95-2.87 (m, 2H), 2.05 (s, 1H), 1.81 (d, J=12.8 Hz, 2H),1.46 (s, 9H), 1.43 (d, J=6.7 Hz, 6H), 1.37 (dd, J=12.1, 4.3 Hz, 2H)

Step 2: Following the procedure for Example 230 starting with tert-butyl(1-(1-isopropyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamategave 270 as a cream solid (78 mg, 40% over three steps). ¹H NMR (400MHz, d₆-DMSO) δ 8.71 (s, 1H), 7.61 (s, 1H), 7.57-7.48 (m, 3H), 7.35-7.23(m, 2H), 4.61-4.51 (m, 1H), 3.35-3.31 (m, 2H), 3.10-2.99 (m, 2H),2.52-2.45 (m, 2H), 1.90-1.72 (m, 2H), 1.35 (d, J=6.6 Hz, 6H), 1.29-1.16(m, 3H). Alkyl NH₂ not seen. LCMS (ES+) m/z 476 (M+1)

Example 2715-amino-2-(2,6-difluorophenyl)-N-(5-((2-hydroxyethyl)(methyl)amino)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide271 Step 1: 2-(Methyl(1-methyl-4-nitro-1H-pyrazol-5-yl)amino)ethanol

Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and2-(methylamino)ethanol gave2-(methyl(1-methyl-4-nitro-1H-pyrazol-5-yl)amino)ethanol as a yellow oil(0.2 g, 81%). ¹H NMR (400 MHz, CDCl₃) δ 8.04 (s, 1H), 3.79 (s, 3H), 3.72(q, J=5.4 Hz, 2H), 3.33 (t, J=5.4 Hz, 2H), 2.93 (s, 3H), 1.91 (t, J=5.4Hz, 1H)

Step 2: Following the procedure for Example 243 starting with2-(methyl(1-methyl-4-nitro-1H-pyrazol-5-yl)amino)ethanol gave 271 as apeach solid (60 mg, 30% over three steps). ¹H NMR (400 MHz, CDCl₃) δ8.91 (s, 1H), 7.77 (s, 1H), 7.37-7.29 (m, 1H), 7.03 (t, J=8.9 Hz, 2H),6.17 (s, 2H), 3.75 (s, 5H), 3.26 (t, J=4.9 Hz, 2H), 2.92 (s, 3H), 2.82(s br, 1H). LCMS (ES+) m/z 409 (M+1)

Example 272(S)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(piperidin-3-yloxy)-1H-pyrazol-4-yl)thiazole-4-carboxamide272 Step 1: (S)-tert-Butyl3-(1-methyl-4-nitro-1H-pyrazol-5-yloxy)piperidine-1-carboxylate

Following the procedure for Example 230, reaction of5-chloro-1-methyl-4-nitro-1H-pyrazole and (S)-tert-butyl3-hydroxypiperidine-1-carboxylate gave (S)-tert-butyl3-(1-methyl-4-nitro-1H-pyrazol-5-yloxy)piperidine-1-carboxylate as apale yellow oil (0.35 g, 97%). ¹H NMR (400 MHz, CDCl₃) δ 8.01 (s, 1H),5.15-4.85 (m, 1H), 3.84-3.72 (m, 2H), 3.69 (s, 3H), 3.41 (d, J=14.2 Hz,1H), 3.30-3.13 (m, 1H), 2.11-2.02 (m, 1H), 1.94-1.82 (m, 2H), 1.63-1.52(m, 1H), 1.42 (s, 9H)

Step 2: Following the procedure for Example 243 starting with(S)-tert-butyl3-(1-methyl-4-nitro-1H-pyrazol-5-yloxy)piperidine-1-carboxylate gave 272as an off-white foam (86 mg, 43% over three steps). ¹H NMR (400 MHz,CDCl₃) δ 9.22 (s, 1H), 7.83 (s, 1H), 7.36-7.29 (m, 1H), 7.02 (t, J=8.6Hz, 2H), 6.19 (s, 2H), 4.21 (s, 1H), 3.71 (s, 3H), 3.02 (s, 2H),2.90-2.72 (m, 2H), 2.00-1.85 (m, 3H), 1.55-1.40 (m, 1H). Alkyl NH notseen. LCMS (ES+) m/z 435 (M+1)

Example 273(R)-5-amino-2-(3-(3-(aminomethyl)pyrrolidin-1-yl)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide273 Step 1: (R)-tert-Butyl2-(3-(3-(butyloxycarbonylaminomethyl)pyrrolidin-1-yl)phenyl)-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

1,3-Dibromobenzene (0.2 g, 0.85 mmol), (R)-tert-butylpyrrolidin-3-ylmethylcarbamate (0.17 g, 0.85 mmol), Pd₂(dba)₃ (39 mg,0.04 mmol), BINAP (40 mg, 0.06 mmol) and sodium tert-butoxide (98 mg,1.02 mmol) were suspended in toluene (2 mL). The mixture was heated at80° C. for 16 hr. The mixture was cooled and diluted with water andEtOAc. The organic layer was separated, passed through a phase separatorcartridge and concentrated under reduced pressure. Purification viasilica gel column chromatography (0-100% EtOAc/isohexane) gave(R)-tert-butyl (1-(3-bromophenyl)pyrrolidin-3-yl)methylcarbamate as ayellow oil (0.179 g, 59%). This oil (0.179 g, 0.5 mmol) was suspended in1,4-dioxane (2 mL). Bis-pinacolato-diboron (0.166 g, 0.66 mmol),potassium acetate (65 mg, 0.66 mmol) and Pd(dppf)Cl₂ (20 mg, 0.025 mmol)were added and the mixture was heated at 100° C. for 16 h. The solutionwas cooled, diluted with DCM and filtered through celite. The solventwas removed under reduced pressure to afford crude (R)-tert-butyl(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-yl)methylcarbamateas a brown oil. A mixture of this oil (0.5 mmol), tert-butyl2-bromo-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate(0.177 g, 0.44 mmol), Na₂CO₃ (0.7 mL, 2M aq. solution, 1.32 mmol) in DME(4.3 mL) was degassed by gently bubbling nitrogen through the mixturefor 15 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II)(72 mg, 0.09 mmol) was added and the mixture degassed for a further 10min before being heated in a microwave at 130° C. for 40 min. Thesolvents were removed under reduced pressure and the residue purifiedvia silica gel column chromatography (0-100% EtOAc/isohexane) to yield(R)-tert-butyl2-(3-(3-(butyloxycarbonylaminomethyl)pyrrolidin-1-yl)phenyl)-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateas a yellow oil (86 mg, 33%). ¹H NMR (400 MHz, CDCl₃) δ 10.38 (s, 1H),8.90 (s, 1H), 7.98 (s, 1H), 7.58 (s, 1H), 7.00 (s, 1H), 6.63-6.57 (m,1H), 4.71-4.69 (m, 1H), 3.92 (s, 3H), 3.59-3.36 (m, 5H), 2.67-2.46 (m,1H), 2.14-2.13 (m, 1H), 1.84-1.80 (m, 1H), 1.55 (s, 9H), 1.54 (s, 9H).Three protons not seen

Step 2: Acidic deprotection of (R)-tert-butyl2-(3-(3-(butyloxycarbonylaminomethyl)pyrrolidin-1-yl)phenyl)-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamategave 273 as an off-white solid (143 mg, 20%). ¹H NMR (400 MHz, d₆-DMSO)δ 9.84 (s, 1H), 8.03 (s, 1H), 7.70 (s, 1H), 7.48 (s, 2H), 7.27 (dd, J=8,7.5 Hz, 1H), 7.12 (dd, J=7.5, 6 Hz, 1H), 7.03-6.97 (m, 1H), 6.61 (dd,J=8, 2 Hz, 1H), 3.86 (s, 3H), 3.51-3.31 (m, 3H), 3.14-3.05 (m, 2H), 2.67(dd, J=7, 3 Hz, 1H), 2.41-2.30 (m, 1H), 2.18-2.08 (m, 1H), 1.84-1.74 (m,1H). Alkyl NH₂ not seen. LCMS (ES+) m/z 398 (M+1)

Example 2745-amino-N-(1-methyl-1H-pyrazol-4-yl)-2-(3-(piperazin-1-yl)phenyl)thiazole-4-carboxamide274

Following Example 278, Suzuki coupling of tert-butyl2-bromo-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate andtert-butyl4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylategave 274 as a pale brown solid (18 mg, 19% over two steps). ¹H NMR (400MHz, d₆-DMSO) δ 9.82 (s, 1H), 7.99 (s, 1H), 7.65 (s, 1H), 7.45 (s, 3H),7.28 (dd, J=8, 7.5 Hz, 1H), 7.19 (d, J=7.5 Hz, 1H), 6.96 (dd, J=8, 2.5Hz, 1H), 3.82 (s, 3H), 3.14 (t, J=5 Hz, 4H), 2.86 (t, J=5 Hz, 4H). AlkylNH not seen. LCMS (ES+) m/z 384 (M+1)

Example 2755-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-carbamoylphenyl)thiazole-4-carboxamide275

Following Example 278, Suzuki coupling of tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateand 2-cyanophenylboronic acid gave 275 as a yellow solid (26 mg, 29%over two steps). ¹H NMR (400 MHz, d₄-MeOD) δ 7.71 (d, J=7.5 Hz, 1H),7.57-7.46 (m, 4H), 3.72 (s, 3H), 3.22-3.11 (m, 4H), 2.61 (d, J=6.5 Hz,2H), 1.84 (d, J=12.1 Hz, 2H), 1.61-1.50 (m, 1H), 1.42-1.29 (m, 2H). LCMS(ES+) m/z 455 (M+1)

Example 2765-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-(dimethylamino)phenyl)thiazole-4-carboxamide276

Following Example 278, Suzuki coupling of tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateand 3-(dimethylamino)phenylboronic acid gave 276 as an off-white solid(34 mg, 37% over two steps). ¹H NMR (400 MHz, d₄-MeOD) δ 7.37-7.34 (m,1H), 7.30 (s, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 6.82(dd, J=8.3, 2.6 Hz, 1H), 3.69 (s, 3H), 3.13-3.04 (m, 4H), 2.97 (s, 6H),2.58 (d, J=6.5 Hz, 2H), 1.80 (d, J=12.5 Hz, 2H), 1.52-1.39 (m, 1H), 1.32(qd, J=11.8, 4.7 Hz, 2H). LCMS (ES+) m/z 455 (M+1)

Example 2775-Amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,5-dichlorophenyl)thiazole-4-carboxamide277

Following Example 278, Suzuki coupling of tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateand 2,5-dichlorobenzeneboronic acid gave 277 as an off-white solid (19mg, 19%). ¹H NMR (400 MHz, d₄-MeOD) δ 8.39 (d, J=2.6 Hz, 1H), 7.51 (d,J=8.6 Hz, 1H), 7.48 (s, 1H), 7.37 (dd, J=8.6, 2.6 Hz, 1H), 3.73 (s, 3H),3.24-3.11 (m, 4H), 2.60 (d, J=6.6 Hz, 2H), 1.85 (d, J=12.5 Hz, 2H),1.55-1.44 (m, 1H), 1.36 (qd, J=11.9, 4.4 Hz, 2H). LCMS (ES+) m/z 464(M+1).

Example 2785-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(4-hydroxy-2-(trifluoromethyl)phenyl)thiazole-4-carboxamide278

A mixture of tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate(0.123 g, 0.20 mmol), Na₂CO₃ (42 mg, 0.40 mmol) and4-hydroxy-2-(trifluoromethyl)benzeneboronic acid (66 mg, 0.32 mmol) inDME (1.5 mL) and water (0.5 mL) was degassed by gently bubbling nitrogenthrough the mixture for 15 min.[1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (16 mg,0.02 mmol) was then added and the mixture degassed for a further 10 minbefore being heated in a microwave at 130° C. for 40 min. The solventswere removed under reduced pressure and the residue purified via silicagel column chromatography (0-100% EtOAc/isohexane). The isolatedintermediate was dissolved in a solution of HCl in 1,4-dioxane (4 M, 2mL) and stirred at room temperature for 16 hr. The solvent was removedunder reduced pressure and the residue purified by preparative HPLC toyield 278 as a pale brown solid (48 mg, 48%). ¹H NMR (400 MHz, d₄-MeOD)δ 7.59 (s, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.15 (d, J=2.5 Hz, 1H), 6.98(dd, J=8.5, 2.5 Hz, 1H), 3.72 (s, 3H), 3.22-3.10 (m, 4H), 2.71 (d, J=6.8Hz, 2H), 1.85 (d, J=12.6 Hz, 2H), 1.66-1.55 (m, 1H), 1.47-1.33 (m, 2H).LCMS (ES+) m/z 496 (M+1).

Example 2795-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-fluoro-2-(trifluoromethyl)phenyl)thiazole-4-carboxamide279

Following Example 278, Suzuki coupling of tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateand 5-fluoro-2-(trifluoromethyl)phenylboronic acid gave 279 as a brownsolid (54 mg, 55% over two steps). ¹H NMR (400 MHz, d₄-MeOD) 7.94 (dd,J=8.9, 5.4 Hz, 1H), 7.60-7.50 (m, 2H), 7.40 (td, J=8.3, 2.6 Hz, 1H),3.73 (s, 3H), 3.21-3.09 (m, 4H), 2.63 (d, J=6.6 Hz, 2H), 1.84 (d, J=12.5Hz, 2H), 1.57-1.48 (m, 1H), 1.38 (qd, J=11.8, 4.7 Hz, 2H). LCMS (ES+)m/z 498 (M+1)

Example 2805-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(4-methoxy-2-(trifluoromethyl)phenyl)thiazole-4-carboxamide280

Following the procedure for Example 337 starting with tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateand 4-methoxy-2-(trifluoromethyl)benzeneboronic acid gave 280 as a brownsolid (56 mg, 54%). ¹H NMR (400 MHz, d₄-MeOD) δ 7.65 (d, J=8.6 Hz, 1H),7.58 (s, 1H), 7.37 (d, J=2.6 Hz, 1H), 7.27 (dd, J=8.6, 2.6 Hz, 1H), 3.94(s, 3H), 3.72 (s, 3H), 3.19-3.06 (m, 4H), 2.62 (d, J=6.5 Hz, 2H), 1.84(d, J=12.5 Hz, 2H), 1.57-1.46 (m, 1H), 1.37 (qd, J=11.7, 4.9 Hz, 2H).LCMS (ES+) m/z 510 (M+1).

Example 2815-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-cyclohexylethyl)thiazole-4-carboxamide281

A mixture of tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate(0.203 g, 0.33 mmol), Na₂CO₃ (70 mg, 0.66 mmol) andtrans-(2-cyclohexylvinyl)boronic acid (0.102 g, 0.66 mmol) in DME (1.5mL) and water (0.5 mL) was degassed by gently bubbling nitrogen throughthe mixture for 15 min.[1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (27 mg,0.033 mmol) was then added and the mixture degassed for a further 10 minbefore being heated in a microwave at 130° C. for 45 min. The reactionmixture was diluted with water and extracted with EtOAc. The combinedorganic extracts were passed through a phase separator cartridge andconcentrated under reduced pressure. The residue was purified via silicagel column chromatography (0-100% EtOAc/isohexane) to afford(E)-tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2-cyclohexylvinyl)thiazol-5-ylcarbamateas a brown gum (0.144 g, 68%). A solution of this gum (0.142 g, 0.22mmol) in MeOH (5 mL) and acetic acid (0.5 mL) was passed through theH-Cube® (70 bar, 70° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge).The solvent was removed under reduced pressure to afford crudetert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2-cyclohexylethyl)thiazol-5-ylcarbamateas a clear gum (0.122 g, 99%). This gum (0.122 g, 0.188 mmol) wasstirred in HCl in 1,4-dioxane (4.0 M, 2 mL) at room temperature for 18hr. The solvents were removed under reduced pressure and the cruderesidue was re-dissolved in MeOH and loaded onto an SCX column. Thecolumn was washed with MeOH and 7 N ammonia in MeOH to yield 281 as apink solid (39 mg, 63%). ¹H NMR (400 MHz, d₄-MeOD) δ 7.43 (s, 1H), 3.71(s, 3H), 3.21-3.06 (m, 4H), 2.86 (t, J=7.8 Hz, 2H), 2.62 (d, J=6.6 Hz,2H), 1.87-1.59 (m, 9H), 1.58-1.45 (m, 1H), 1.43-1.15 (m, 6H), 0.99 (q,J=11.9 Hz, 2H). LCMS (ES+) m/z 446 (M+1)

Example 2825-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cyclohexylthiazole-4-carboxamide282

Following the procedure for Example 281, Suzuki coupling of tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateand cyclohex-1-ene-1-boronic acid gave 282 (44 mg, 51% over threesteps). ¹H NMR (400 MHz, d₄-MeOD) δ 7.45 (s, 1H), 3.71 (s, 3H),3.21-3.08 (m, 4H), 2.85-2.76 (m, 1H), 2.64 (d, J=6.6 Hz, 2H), 2.09 (d,J=12.1 Hz, 2H), 1.90-1.81 (m, 4H), 1.76 (d, J=13.0 Hz, 1H), 1.59-1.25(m, 8H). LCMS (ES+) m/z 418 (M+1)

Example 2835-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide283

A solution of tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate(0.15 g, 0.244 mmol) in MeOH (5 mL) and acetic acid (0.5 mL) was passedthrough the H-Cube® (70 bar, 70° C., flow rate: 1 mL/min, 30 mm 10% Pd/Ccartridge). The solvent was removed under reduced pressure to affordcrude tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateas a clear gum (98 mg, 96%). This gum (97 mg, 0.182 mmol) was stirred inHCl in 1,4-dioxane (4.0 M, 2 mL) at room temperature for 18 hr. Thesolvents were removed under reduced pressure and the crude residue wasre-dissolved in MeOH and loaded onto an SCX column. The column waswashed with MeOH and 7 N ammonia in MeOH to give 283 as an off-whitesolid (39 mg, 84%). ¹H NMR (400 MHz, d₄-MeOD) δ 7.97 (s, 1H), 7.44 (s,1H), 3.71 (s, 3H), 3.21-3.07 (m, 4H), 2.65 (d, J=6.6 Hz, 2H), 1.83 (d,J=12.5 Hz, 2H), 1.60-1.47 (m, 1H), 1.43-1.30 (m, 2H). LCMS (ES+) m/z 336(M+1)

Example 284(R)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(piperidin-3-yloxy)-1H-pyrazol-4-yl)thiazole-4-carboxamide284 Step 1: (R)-tert-Butyl3-(1-methyl-4-nitro-1H-pyrazol-5-yloxy)piperidine-1-carboxylate

Following the procedure for Example 230, reaction of5-chloro-1-methyl-4-nitro-1H-pyrazole and (R)-tert-butyl3-hydroxypiperidine-1-carboxylate gave (R)-tert-butyl3-(1-methyl-4-nitro-1H-pyrazol-5-yloxy)piperidine-1-carboxylate as apale yellow oil (0.34 g, 93%). ¹H NMR (400 MHz, CDCl₃) δ 8.01 (s, 1H),5.15-4.85 (m, 1H), 3.84-3.72 (m, 2H), 3.69 (s, 3H), 3.41 (d, J=14.2 Hz,1H), 3.30-3.13 (m, 1H), 2.11-2.02 (m, 1H), 1.94-1.82 (m, 2H), 1.63-1.52(m, 1H), 1.42 (s, 9H)

Step 2: Following the procedure for Example 243, (R)-tert-butyl3-(1-methyl-4-nitro-1H-pyrazol-5-yloxy)piperidine-1-carboxylate wasconverted to 284 (145 mg, 68% over three steps). ¹H NMR (400 MHz, CDCl₃)δ 9.29 (s, 1H), 7.86 (s, 1H), 7.38-7.23 (m, 1H), 7.02 (t, J=8.6 Hz, 2H),6.18 (s, 2H), 4.18 (s, 1H), 3.71 (s, 3H), 3.08-2.90 (m, 2H), 2.85-2.70(m, 1H), 2.81-2.71 (m, 1H), 2.00-1.87 (s, 3H), 1.50-1.35 (m, 1H). AlkylNH not seen. LCMS (ES+) m/z 435 (M+1)

Example 2855-amino-2-(3-(4-(aminomethyl)piperidin-1-yl)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide285 Step 1: tert-Butyl2-(3-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)phenyl)-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

Following the procedure for Example 273 starting with 1,3-dibromobenzeneand tert-butyl piperidin-4-ylmethylcarbamate and tert-butyl2-bromo-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate gavetert-butyl2-(3-(4-(butyloxycarbonyl-aminomethyl)piperidin-1-yl)phenyl)-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateas a yellow oil (138 mg, 71%). ¹H NMR (400 MHz, CDCl₃) δ 10.37 (s, 1H),8.89 (s, 1H), 7.98 (s, 1H), 7.59 (s, 1H), 7.42 (s, 1H), 7.39-7.36 (m,1H), 7.31 (t, J=7.9 Hz, 1H), 7.03-6.97 (m, 1H), 4.61-4.61 (m, 1H), 3.92(s, 3H), 3.80-3.75 (m, 2H), 3.14-3.01 (m, 2H), 2.79-2.74 (m, 2H),1.89-1.79 (m, 2H), 1.56-1.53 (m, 18H), 1.43-1.40 (m, 2H). One proton notseen

Step 2: Deprotection of tert-butyl2-(3-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)phenyl)-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateunder acidic conditions gave 285 as an off-white solid (12 mg, 17%). ¹HNMR (400 MHz, d₆-DMSO) δ 9.80 (s, 1H), 7.98 (s, 1H), 7.65-7.63 (m, 1H),7.46-7.42 (m, 3H), 7.27 (t, J=7.8 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H), 6.98(dd, J=7.8, 2.4 Hz, 1H), 3.86-3.75 (m, 5H), 2.70 (dd, J=12.9, 10.7 Hz,2H), 2.50-2.42 (m, 2H), 1.86-1.72 (m, 4H), 1.42-1.35 (m, 1H), 1.23 (qd,J=12.1, 3.9 Hz, 2H). LCMS (ES+) m/z 412 (M+1)

Example 2865-amino-N-(5-(4,4-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide286 Step 1: 4,4-Difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepane

Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and4,4-difluoroazepane gave4,4-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepane as a whitesolid (0.41 g, 100%). ¹H NMR (400 MHz, CDCl₃) δ 8.04 (s, 1H), 3.79 (s,3H), 3.39-3.23 (m, 4H), 2.35-2.20 (m, 4H), 2.00-1.92 (m, 2H)

Step 2: Following the procedure for Example 243 starting with4,4-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepane gave 286 as awhite solid (90 mg, 12% over three steps). ¹H NMR (400 MHz, CDCl₃) δ8.54 (s, 1H), 7.84 (s, 1H), 7.32 (tt, J=8.5, 6.0 Hz, 1H), 7.05-6.98 (m,2H), 6.12 (s, 2H), 3.75 (s, 3H), 3.30-3.23 (m, 4H), 2.33-2.18 (m, 4H),1.95-1.87 (m, 2H). LCMS (ES+) m/z 469 (M+1)

Example 2875-Amino-2-(2,6-difluorophenyl)-N-(5-(3,3-difluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide287

To a solution of tert-butyl2-(2,6-difluorophenyl)-4-(5-(3,3-difluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate(57 mg, 0.1 mmol) in MeOH (2 mL) was added HCl in 1,4-dioxane (4 M, 5mL). After stirring at room temperature for 18 hr the mixture wasconcentrated under reduced pressure. Purification via preparative HPLCgave 287 as a white solid (29 mg, 63%). ¹H NMR (400 MHz, CDCl₃) δ 8.40(s, 1H), 7.65 (s, 1H), 7.37-7.28 (m, 1H), 7.06-6.99 (m, 2H), 6.13 (s,2H), 3.75 (s, 3H), 3.32 (t, J=11.0 Hz, 2H), 3.17-3.12 (m, 2H), 2.08-1.95(m, 2H), 1.92-1.84 (m, 2H). LCMS (ES+) m/z 455.0 (M+1).

Example 2885-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(3-oxopiperazin-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide288 Step 1: 4-(1-Methyl-4-nitro-1H-pyrazol-5-yl)piperazin-2-one

Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and piperazin-2-onegave 4-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperazin-2-one as a whitesolid (166 mg, 100%). ¹H NMR (400 MHz, d₆-DMSO) δ 8.21 (s, 1H), 8.09 (s,1H), 3.78 (s, 3H), 3.44-3.30 (m, 6H)

Step 2: Following the procedure for Example 243 starting with4-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperazin-2-one gave 288 as a whitesolid (15 mg, 5% over three steps). ¹H NMR (400 MHz, CDCl₃) δ 8.54 (s,1H), 7.84 (s, 1H), 7.32 (tt, J=8.5, 6.0 Hz, 1H), 7.05-6.98 (m, 2H), 6.12(s, 2H), 3.75 (s, 3H), 3.30-3.23 (m, 2H), 2.33-2.18 (m, 2H), 1.95-1.87(m, 2H). LCMS (ES+) m/z 434 (M+1)

Example 2895-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cyclopentylthiazole-4-carboxamide289

A mixture of tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate(0.200 g, 0.62 mmol), Na₂CO₃ (0.200 g, 1.86 mmol) and cyclopentent-1-eneboronic acid (0.208 g, 1.86 mmol) in DME (3 mL) and water (1 mL) wasdegassed by gently bubbling nitrogen through the mixture for 15 min.[1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (76 mg,0.09 mmol) was then added and the mixture degassed for a further 10 minbefore being heated at 80° C. for 16 hr. The reaction mixture wasdiluted with water and extracted with EtOAc. The aqueous layer wasacidified to pH 5 with citric acid and extracted with DCM. The combinedorganic extracts were passed through a phase separator cartridge andconcentrated under reduced pressure to give5-(tert-butyloxycarbonylamino)-2-cyclopentenylthiazole-4-carboxylic acidas a black solid (0.190 g, 99%). This acid (0.184 g, 0.59 mmol) wasadded to a solution of5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-amine (0.108 g,0.35 mmol), DIPEA (0.097 mL, 0.56 mmol) and PyBOP (0.255 g, 0.49 mmol)in DCM (6 mL) and the mixture was stirred at room temperature for 18 hr.The mixture was diluted with DCM and washed with water. The organiclayer was separated, dried over MgSO₄ and the solvent removed underreduced pressure. Purification via silica gel column chromatography(0-10% MeOH/DCM) gave tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-cyclopentenylthiazol-5-ylcarbamateas a brown solid (0.165 g, 78%). A solution of this solid (0.162 g, 0.27mmol) in MeOH (5 mL) and acetic acid (0.4 mL) was passed through theH-Cube® (70 bar, 70° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge).The solvent was removed under reduced pressure to afford crudetert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-cyclopentylthiazol-5-ylcarbamateas a clear gum (84 mg, 51%). This gum (81 mg, 0.13 mmol) was stirred inHCl in 1,4-dioxane (4 M, 2 mL) at room temperature for 18 hr. Thesolvents were removed under reduced pressure and the crude residue wasre-dissolved in MeOH and loaded onto an SCX column. The column waswashed with MeOH and eluted with 7 N ammonia in MeOH. The residue wasfurther purified via silica gel column chromatography (0-10% MeOH/DCM)to afford 289 as a yellow solid (19 mg, 35%). ¹H NMR (400 MHz, d₄-MeOD)δ 7.46 (s, 1H), 3.71 (s, 3H), 3.30-3.23 (m, 1H), 3.21-3.08 (m, 4H), 2.62(d, J=6.6 Hz, 2H), 2.17-2.07 (m, 2H), 1.89-1.66 (m, 8H), 1.58-1.45 (m,1H), 1.44-1.29 (m, 2H). LCMS (ES+) m/z 404 (M+1)

Example 2905-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)thiazole-4-carboxamide290

Following the procedure for Example 281, tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateand 3,4-dihydro-2H-pyran-6-boronic acid pinacol ester gave 290 as ayellow solid (27 mg, 20% over three steps). ¹H NMR (400 MHz, d₄-MeOD) δ7.34 (s, 1H), 4.46-4.41 (m, 1H), 4.02-3.95 (m, 1H), 3.63 (s, 3H),3.67-3.51 (m, 1H), 3.12-2.97 (m, 4H), 2.53 (d, J=6.6 Hz, 2H), 2.07-1.98(m, 1H), 1.97-1.79 (m, 1H), 1.76 (d, J=12.5 Hz, 2H), 1.68-1.53 (m, 4H),1.49-1.36 (m, 1H), 1.36-1.21 (m, 2H). LCMS (ES+) m/z 420 (M+1)

Example 291(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-cyclopropyl-2-fluoro-3-methylphenyl)thiazole-4-carboxamide291 Step 1:2-(5-bromo-2-fluoro-3-methylphenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

To a 50 mL round bottom flask equipped with a stir bar was added5-bromo-2-fluoro-3-methylphenylboronic acid (1.0 g, 4.3 mmol),N-methyliminodiacetic acid (0.76 g, 5.2 mmol), toluene (8 mL) and DMSO(2 mL). The flask was fitted with a Dean-Stark trap and the Dean-Starktrap was fitted with a reflux condenser. The mixture was heated toreflux with azeotropic removal of water for 4.5 h. The solution wasconcentrated in vacuo. The residue was absorbed on Celite in vacuo froman acetone suspension and the resulting powder was subjected to Iscoflash chromatography eluted with 0 to 70% acetonitrile in ether to give2-(5-bromo-2-fluoro-3-methylphenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione(1.26 g, 86%).

Step 2:2-(5-cyclopropyl-2-fluoro-3-methylphenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

In a microwave reaction vessel equipped with stir bar was charged2-(5-bromo-2-fluoro-3-methylphenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione(300 mg, 0.9 mmol), cyclopropylboronic acid (220 mg, 2.6 mmol),palladium acetate (14 mg, 0.06 mmol), S-Phos (50 mg, 0.12 mmol) andpotassium phosphate (560 mg, 2.6 mmol). Degassed toluene (15 mL) wasadded. The reaction was heated under microwave at 120° C. for 15 min.LCMS indicated completion of the reaction. The mixture was diluted withacetonitrile and filtered through a pad of Celite and washed withcopious amount of acetonitrile. The filtrate was concentrated in vacuoand the residue was absorbed on Celite from an acetone solution. Theresulting powder was subjected to Isco flash chromatography eluted with0 to 70% acetonitrile in ether to give a light yellow oil,2-(5-cyclopropyl-2-fluoro-3-methylphenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione(167 mg, 60%).

Step 3: (R)-tert-butyl4-(5-(4-Cbz-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(5-cyclopropyl-2-fluoro-3-methylphenyl)thiazol-5-ylcarbamate

In a microwave reaction vessel, (R)-tert-butyl4-(5-(4-Cbz-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate(130 mg, 0.2 mmol),2-(5-cyclopropyl-2-fluoro-3-methylphenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione(167 mg, 0.55 mmol), S-Phos (13.2 mg, 0.032 mmol) and palladium acetate(3.6 mg, 0.016 mmol) were dissolved in 1,4-dioxane (4.0 mL). The cap wasclosed and the reaction vessel was vacuum purged with nitrogen threetimes. Potassium phosphate (3.0M aq., 0.27 mL, 0.81 mmol, degassedbefore use) was added and mixture was stirred at room temperature for 10min before heated under microwave at 120° C. for 20 min. The mixture wasdiluted with methanol and filtered through a pad of Celite and washedwith copious amount of methylene chloride. The filtrate was concentratedin vacuo and purified on flash chromatography (Isco Co.) eluted with 0to 5% methanol in methylene chloride to give (R)-tert-butyl4-(5-(4-Cbz-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(5-cyclopropyl-2-fluoro-3-methylphenyl)thiazol-5-ylcarbamate(82 mg, 57%).

Step 4: To a 25 mL round bottom flask was added the (R)-tert-butyl4-(5-(4-Cbz-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(5-cyclopropyl-2-fluoro-3-methylphenyl)thiazol-5-ylcarbamate(82 mg, 0.11 mmol), methylene chloride (4 mL) and a 1M solution of borontribromide in CH₂Cl₂ (0.46 mL, 0.46 mmol). The mixture was stirred atroom temperature overnight. The solvent was distilled off and theresidue was basified with saturated sodium bicarbonate. The aqueoussolution was extracted with ethyl acetate 3×. The combined organiclayers were dried over sodium sulfate, filtered and concentrated. Thecrude product was purified via reverse phase HPLC to afford 291 (2.8 mg,5%). MS (ESI) m/z: 484.2 [M+H⁺].

Example 292(R)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-bromopicolinamide292

Following procedures from Examples 141, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16was converted to 292. ¹H NMR (400 MHz, DMSO) δ 8.10 (d, J=7.5 Hz, 1H),7.99 (t, J=7.7 Hz, 1H), 7.90 (d, J=7.9 Hz, 1H), 7.56 (s, 1H), 3.66 (s,3H), 3.20-3.03 (m, 5H), 1.95-1.76 (m, 3H), 1.73-1.48 (m, 3H). MS (ESI)m/z: 393.1/395.1 [M+H⁺].

Example 293(R)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide293

Following procedures from Examples 141, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16was converted to 293. ¹H NMR (400 MHz, DMSO) δ 8.21-8.07 (m, 3H), 8.04(d, J=7.6 Hz, 1H), 7.68 (s, 1H), 7.63-7.51 (m, 1H), 7.47-7.32 (m, 2H),3.67 (s, 3H), 3.21-3.04 (m, 5H), 2.96 (td, J=8.8, 4.4 Hz, 1H), 1.79(ddd, J=24.4, 13.7, 5.6 Hz, 4H), 1.66-1.39 (m, 4H). MS (ESI) m/z: 409.2[M+H⁺].

Example 2945-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(3-oxo-1,4-diazepan-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide294 Step 1: 4-(1-Methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepan-2-one

Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 1,4-diazepan-2-onegave 4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepan-2-one as anoff-white solid (0.27 g, 92%). ¹H NMR (400 MHz, CDCl₃) δ 8.02 (s, 1H),6.10 (s, 1H), 3.95-3.86 (m, 2H), 3.80 (s, 3H), 3.51-3.44 (m, 2H),3.43-3.37 (m, 2H), 2.04-1.97 (m, 2H)

Step 2: Following the procedure for Example 243 starting with4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepan-2-one gave 294 as awhite solid (67 mg, 11% over three steps). ¹H NMR (400 MHz, CDCl₃) δ8.47 (s, 1H), 7.71 (s, 1H), 7.33 (tt, J=8.5, 6.0 Hz, 1H), 7.06-6.99 (m,2H), 6.12 (s, 2H), 5.94 (t, J=6.0 Hz, 1H), 3.77 (s, 3H), 3.48-3.42 (m,2H), 3.33-3.26 (m, 4H), 2.82-2.76 (m, 2H). LCMS (ES+) m/z 448 (M+1)

Example 2955-amino-2-(2,6-difluorophenyl)-N-(5-(3-fluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide295 Step 1: 3-Fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine

Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 3-fluoropiperidinehydrochloride gave3-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine as a yellow oil(0.27 g, 97%). ¹H NMR (400 MHz, CDCl₃) δ 8.02 (s, 1H), 4.88-4.71 (m,1H), 3.79 (s, 3H), 3.47 (ddd, J=29.8, 12.8, 2.1 Hz, 1H), 3.32-3.15 (m,2H), 3.07-2.99 (m, 1H), 2.11-1.99 (m, 2H), 1.95-1.76 (m, 1H), 1.74-1.62(m, 1H)

Step 2: Following the procedure for Example 243 starting with3-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine gave 295 as awhite solid (19 mg, 3% over three steps). ¹H NMR (400 MHz, CDCl₃) δ 8.46(s, 1H), 7.71 (s, 1H), 7.37-7.28 (m, 1H), 7.08-6.98 (m, 2H), 6.12 (s,2H), 4.83-4.65 (m, 1H), 3.74 (s, 3H), 3.37 (ddd, J=22.0, 12.0, 3.0 Hz,1H), 3.27-3.19 (m, 1H), 3.14-3.08 (m, 2H), 2.02-1.83 (m, 3H), 1.71-1.63(m, 1H). LCMS (ES+) m/z 437 (M+1)

Example 2965-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(4-methylpiperazin-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide296 Step 1: 1-Methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperazine

Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and N-methylpiperazine gave 1-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperazineas an oil (0.18 g, 65%). ¹H NMR (400 MHz, CDCl₃) δ 8.02 (s, 1H), 3.77(s, 3H), 3.26 (t, J=4.6 Hz, 4H), 2.60-2.53 (m, 4H), 2.38 (s, 3H)

Step 2: Following the procedure for Example 243 starting with1-methyl-4-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperazine gave 296 as abeige solid (19 mg, 3% over three steps). ¹H NMR (400 MHz, CDCl₃) δ 8.43(s, 1H), 7.69 (s, 1H), 7.36-7.28 (m, 1H), 7.06-6.97 (m, 2H), 6.12 (s,2H), 3.75 (s, 3H), 3.18 (t, J=4.5 Hz, 4H), 2.53-2.59 (m, 4H), 2.36 (s,3H). LCMS (ES+) m/z 434 (M+1)

Example 2975-Amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-fluoro-2-hydroxyphenyl)thiazole-4-carboxamide297

Following the procedure for Example 278 starting with tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateand 5-fluoro-2-hydroxyphenylboronic acid gave 297 as an off-white solid(18 mg, 20%). ¹H NMR (400 MHz, d₄-MeOD) δ 7.64 (dd, J=9.6, 3.1 Hz, 1H),7.49 (s, 1H), 6.96 (td, J=4.8, 3.1 Hz, 1H), 6.90 (dd, J=9.6, 4.8 Hz,1H), 3.74 (s, 3H), 3.27-3.12 (m, 4H), 2.66 (d, J=6.5 Hz, 2H), 1.86 (d,J=12.5 Hz, 2H), 1.69-1.42 (m, 1H), 1.45-1.36 (m, 2H). LCMS (ES+) m/z 446(M+1).

Example 2985-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-cyano-2-fluorophenyl)thiazole-4-carboxamide298

Following Example 278, Suzuki coupling of tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateand 5-cyano-2-fluorophenylboronic acid gave 298 as a yellow solid (32mg, 35% over two steps). ¹H NMR (400 MHz, d₄-MeOD) 8.75 (dd, J=6.9, 2.2Hz, 1H), 7.80-7.75 (m, 1H), 7.51-7.45 (m, 2H), 3.74 (s, 3H), 3.25-3.11(m, 4H), 2.60 (d, J=6.6 Hz, 2H), 1.87 (d, J=12.5 Hz, 2H), 1.53-1.49 (m,1H), 1.43-1.32 (m, 2H). LCMS (ES+) m/z 455 (M+1)

Example 2995-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cycloheptylthiazole-4-carboxamide299

Following the procedure for Example 281 starting with tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateand 1-cycloheptenylboronic acid pinacol ester gave 299 as an off-whitesolid (24 mg, 30% over three steps). ¹H NMR (400 MHz, d₄-MeOD) δ 7.46(s, 1H), 3.72 (s, 3H), 3.21-3.08 (m, 4H), 3.07-2.96 (m, 1H), 2.66 (d,J=6.7 Hz, 2H), 2.18-2.09 (m, 2H), 1.85-1.46 (m, 13H), 1.44-1.30 (m, 2H).LCMS (ES+) m/z 432 (M+1)

Example 3005-amino-N-(5-(4-cyanopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide300 Step 1:1-(1-Methyl-4-nitro-1H-pyrazol-5-yl)piperidine-4-carbonitrile

Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 4-cyanopiperidinegave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine-4-carbonitrile as anoff-white solid (0.23 g, 79%). ¹H NMR (400 MHz, CDCl₃) δ 8.03 (s, 1H),3.78 (s, 3H), 3.35-3.19 (m, 4H), 2.88-2.79 (m, 1H), 2.19-2.11 (m, 2H),2.06-1.95 (m, 2H)

Step 2: Following the procedure for Example 243 starting with1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine-4-carbonitrile gave 300as a white solid (14 mg, 3% over three steps). ¹H NMR (400 MHz, CDCl₃) δ8.48 (s, 1H), 7.72 (s, 1H), 7.36-7.29 (m, 1H), 7.09-7.00 (m, 2H), 6.11(s, 2H), 3.74 (s, 3H), 3.31-3.24 (m, 2H), 3.17-3.09 (m, 2H), 2.78-2.70(m, 1H), 2.14-1.96 (m, 4H). LCMS (ES+) m/z 444 (M+1)

Example 3015-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-isopropylphenyl)thiazole-4-carboxamide301

Following Example 278, Suzuki coupling of tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateand 3-isopropylbenzeneboronic acid gave 301 as the mono-formate salt asa red gum (38 mg, 41% over two steps). ¹H NMR (400 MHz, d₆-DMSO withD₂O) δ 8.35 (s, 1H), 7.70 (s, 1H), 7.58 (d, J=7.7 Hz, 1H), 7.37 (t,J=7.7 Hz, 1H), 7.32-7.25 (m, 2H), 3.62 (s, 3H), 3.10 (d, J=11.5 Hz, 2H),3.04-2.88 (m, 3H), 2.72 (d, J=6.9 Hz, 2H), 1.73 (d, J=12.6 Hz, 2H),1.64-1.58 (m, 1H), 1.34-1.24 (m, 2H), 1.22 (d, J=6.9 Hz, 6H). LCMS (ES+)m/z 454 (M+1)

Example 302(R)-3-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)picolinamide302

Following procedures from Example 229, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16was converted to 302. ¹H NMR (400 MHz, DMSO) δ 9.74 (br, 1H), 7.84 (d,J=4.1 Hz, 1H), 7.55 (s, 1H), 7.28 (dd, J=8.4, 4.2 Hz, 1H), 7.20 (d,J=8.4 Hz, 1H), 6.85 (br, 2H), 3.64 (s, 3H), 3.20-2.93 (m, 5H), 1.88-1.75(m, 3H), 1.70-1.41 (m, 3H). MS (ESI) m/z: 330.2 [M+H⁺].

Example 303(R)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropicolinamide303

Following procedures from Examples 140, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16was converted to 303. ¹H NMR (400 MHz, DMSO) δ 8.70 (d, J=2.8 Hz, 1H),8.17 (dd, J=8.7, 4.7 Hz, 1H), 7.94 (td, J=8.7, 2.8 Hz, 1H), 7.48 (s,1H), 3.65 (s, 3H), 3.20-2.96 (m, 6H), 1.92-1.70 (m, 3H), 1.64-1.42 (m,3H). MS (ESI) m/z: 333.2 [M+H⁺].

Example 3045-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cyclopropylthiazole-4-carboxamide304 Step 1:5-(tert-Butoxycarbonylamino)-2-cyclopropylthiazole-4-carboxylic acid

Reaction of ethyl 2-amino-2-cyanoacetate and cyclopropanecarbonylchloride gave5-(tert-butoxycarbonylamino)-2-cyclopropylthiazole-4-carboxylic acid asa yellow solid (0.31 g, 14% over four steps). ¹H NMR (400 MHz, d₆-DMSO)δ 9.97 (s, 1H), 2.32-2.24 (m, 1H), 1.49 (s, 9H), 1.09-1.03 (m, 2H),0.95-0.89 (m, 2H). OH not seen

Step 2: To a solution of5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-amine (99 mg,0.32 mmol) in DCM (6 mL) was added DIPEA (0.09 mL, 0.51 mmol), PyBOP(0.233 g, 0.44 mmol) and5-(tert-butoxycarbonylamino)-2-cyclopropylthiazole-4-carboxylic acid (95mg, 0.34 mmol) and the mixture was stirred at room temperature for 18hr. The mixture was diluted with DCM and washed with water. The organiclayer was separated, dried over MgSO₄ and the solvent removed underreduced pressure. Purification via silica gel column chromatography(0-10% MeOH/DCM) gave tert-butyl4-(5-(4-(butyloxycarbonyl-aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-cyclopropylthiazol-5-ylcarbamateas a red gum (0.131 g, 71%). This gum (0.127 g, 0.22 mmol) was stirredin HCl in 1,4-dioxane (4.0 M, 2 mL) at room temperature for 18 hr. Thesolvents were removed under reduced pressure and the crude residuepurified by preparative HPLC to afford 304 as a white solid (41 mg,50%). ¹H NMR (400 MHz, d₄-MeOD) δ 7.43 (s, 1H), 3.71 (s, 3H), 3.20-3.05(m, 4H), 2.61 (d, J=6.6 Hz, 2H), 2.17-2.08 (m, 1H), 1.84 (d, J=12.6 Hz,2H), 1.57-1.45 (m, 1H), 1.35 (qd, J=11.9, 4.4 Hz, 2H), 1.09-1.02 (m,2H), 0.98-0.92 (m, 2H). LCMS (ES+) m/z 376 (M+1)

Example 3055-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cyclobutylthiazole-4-carboxamide305 Step 1:5-(tert-Butoxycarbonylamino)-2-cyclobutylthiazole-4-carboxylic acid

Following the procedure for Examples 19-23 starting with ethyl2-amino-2-cyanoacetate and cyclobutane carbonyl chloride gave5-(tert-butoxycarbonylamino)-2-cyclobutylthiazole-4-carboxylic acid as abrown gum (0.24 g, 10% over four steps). ¹H NMR (400 MHz, d₆-DMSO) δ3.69-3.61 (m, 1H), 2.35-2.27 (m, 2H), 2.24-2.17 (m, 2H), 2.02-1.94 (m,1H), 1.87-1.82 (m, 1H), 1.46 (s, 9H). NH and OH not seen

Step 2: Following the procedure for Example 304 starting with5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-amine and5-(tert-butoxycarbonylamino)-2-cyclobutylthiazole-4-carboxylic acid gave305 as a white solid (44 mg, 37% over two steps). ¹H NMR (400 MHz,d₄-MeOD) δ 7.45 (s, 1H), 3.75-3.62 (m, 4H), 3.23-3.07 (m, 4H), 2.60 (d,J=6.5 Hz, 2H), 2.47-2.29 (m, 4H), 2.17-2.01 (m, 1H), 2.00-1.90 (m, 1H),1.84 (d, J=12.5 Hz, 2H), 1.56-1.43 (m, 1H), 1.36 (qd, J=11.9, 4.4 Hz,2H). LCMS (ES+) m/z 390 (M+1)

Example 3065-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(piperidin-4-ylamino)-1H-pyrazol-4-yl)thiazole-4-carboxamide306 Step 1: tert-Butyl4-(1-methyl-4-nitro-1H-pyrazol-5-ylamino)piperidine-1-carboxylate

Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and tert-butyl4-aminopiperidine-1-carboxylate gave tert-butyl4-(1-methyl-4-nitro-1H-pyrazol-5-ylamino)piperidine-1-carboxylate as apale yellow solid (0.23 g, 57%). ¹H NMR (400 MHz, CDCl₃) δ 7.91 (s, 1H),6.40 (d, J=9.8 Hz, 1H), 4.06-3.95 (m, 2H), 3.81 (s, 3H), 3.70-3.59 (m,1H), 3.05-2.93 (m, 2H), 2.00-1.92 (m, 2H), 1.60-1.50 (m, 2H), 1.49 (s,9H)

Step 2: Following the procedure for Example 243 starting with tert-butyl4-(1-methyl-4-nitro-1H-pyrazol-5-ylamino)piperidine-1-carboxylate gave306 as a beige solid (90 mg, 60% over three steps). ¹H NMR (400 MHz,CDCl₃) δ 8.45 (s, 1H), 7.48 (s, 1H), 7.41-7.23 (m, 1H), 7.02 (t, J=8.8Hz, 2H), 6.17 (s, 2H), 3.75 (s, 3H), 7.74-3.68 (m, 1H), 3.08 (d, J=12.4Hz, 2H), 3.00-2.85 (m, 1H), 2.58 (t, J=11.8 Hz, 2H), 1.92 (d, J=13.7 Hz,2H), 1.37 (q, J=11.8 Hz, 2H). Alkyl NH not seen. LCMS (ES+) m/z 434(M+1)

Example 3075-amino-2-(2,6-difluorophenyl)-N-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)thiazole-4-carboxamide307 Step 1: tert-Butyl7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazole-1-carboxylate

To a solution of 2,3-dihydro-1H-pyrazolo[1,5-a]imidazole (1 g, 9.17mmol) in conc. H₂SO₄ (aq.) at 0° C. was added conc. HNO₃ (aq.)portion-wise over 15 min. The reaction was warmed to room temperatureand the mixture was stirred for 18 h. The mixture was poured into icewater (200 mL) with stirring. The product was extracted into DCM and thecombined organics were washed with saturated aqueous NaHCO₃. The organiclayer was separated, passed through a phase separator cartridge andconcentrated under reduced pressure. The crude residue was trituratedwith diethyl ether to yield7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazole as a pale brown solid(0.52 g, 34%). Sodium hydride (60% dispersion in mineral oil, 0.065 g,1.62 mmol) was added in 2 portions to a stirred solution of7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazole (0.21 g, 1.35 mmol) inanhydrous DMF (10 mL) at room temperature under a nitrogen atmosphere.The mixture was stirred for 10 min. before di-tert-butyl dicarbonate(0.68 mL, 2.75 mmol) was added. The reaction was stirred for 45 min.Water (5 mL) was added dropwise and the mixture concentrated underreduced pressure. The residue was diluted with water and the productextracted into diethyl ether. The combined organics were dried overMgSO₄ and concentrated under reduced pressure. The crude residue waspurified via silica gel chromatography (0-100% EtOAc/isohexane) to givetert-butyl 7-nitro-2,3-dihydro-1H-pyrazolo[1,5-c]imidazole-1-carboxylateas a grey solid (0.22 g, 63%). ¹H NMR (400 MHz, CDCl₃) δ 7.89 (s, 1H),4.60-4.53 (m, 2H), 4.38-4.30 (m, 2H), 1.50 (s, 9H)

Step 2: Following the procedure for Example 230 starting with tert-butyl7-nitro-2,3-dihydro-1H-pyrazolo[1,5-c]imidazole-1-carboxylate gave 307as a cream solid (26 mg, 8% over three steps). ¹H NMR (400 MHz, d₆-DMSO)δ 9.20 (s, 1H), 7.65-7.45 (m, 3H), 7.36 (s, 1H), 7.27 (t, J=8.7 Hz, 2H),5.26 (s, 1H), 4.06 (t, J=7.9 Hz, 2H), 3.84 (t, J=7.9 Hz, 2H). LCMS (ES+)m/z 363 (M+1)

Example 308(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-bromo-2-fluorophenyl)thiazole-4-carboxamide308 Following procedures from Examples 140, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16and the product of Example 27,245-bromo-2-fluorophenyl)-5-(tert-butoxycarbonylamino)thiazole-4-carboxylicacid, were converted to 308. ¹H NMR (400 MHz, DMSO) δ 9.05 (s, 1H), 8.45(dd, J=6.7, 2.5 Hz, 1H), 7.66-7.55 (m, 1H), 7.48 (s, 2H), 7.43 (s, 1H),7.36 (dd, J=11.2, 8.9 Hz, 1H), 3.65 (s, 4H), 3.21-2.93 (m, 7H), 1.84(dd, J=8.2, 3.6 Hz, 3H), 1.72-1.39 (m, 3H). MS (ESI) m/z: 508.1/510.1[M+H⁺]. Example 309(R)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)picolinamide 309

Following procedures from Examples 140, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16was converted to 309. ¹H NMR (400 MHz, DMSO) δ 9.86 (s, 1H), 8.71 (d,J=4.6 Hz, 1H), 8.40 (s, 1H), 8.16-7.97 (m, 2H), 7.71-7.58 (m, 1H), 7.48(s, 1H), 3.67 (s, 5H), 3.25-2.98 (m, 8H), 2.04-1.51 (m, 7H). MS (ESI)m/z: 315.2 [M+H⁺].

Example 310(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-isopropyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide310 Step 1: 5-Chloro-1-isopropyl-4-nitro-1H-pyrazole

Chlorination of 1-isopropyl-4-nitro-1H-pyrazole gave5-chloro-1-isopropyl-4-nitro-1H-pyrazole as a colourless solid (1.43 g,75%). ¹H NMR (400 MHz, CDCl₃) δ 8.18 (s, 1H), 4.80-4.72 (m, 1H), 1.53(d, J=6.4 Hz, 6H).

Step 2:(R)-2,2,2-Trifluoro-N-(1-(1-isopropyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)acetamide

Reaction of 5-chloro-1-isopropyl-4-nitro-1H-pyrazole and(R)—N-(azepan-4-yl)-2,2,2-trifluoroacetamide gave(R)-2,2,2-trifluoro-N-(1-(1-isopropyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)acetamideas a pale yellow gum (90 mg, 52%). ¹H NMR (400 MHz, CDCl₃) δ 8.08 (s,1H), 6.39 (s, 1H), 4.83-4.70 (m, 1H), 4.24-4.17 (m, 1H), 3.45-3.32 (m,1H), 3.28-3.12 (m, 3H), 2.23-2.02 (m, 2H), 2.00-1.80 (m, 4H), 1.54-1.44(m, 6H)

Step 3: Following the procedure for Example 230 starting with(R)-2,2,2-trifluoro-N-(1-(1-isopropyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)acetamidegave 310 as a cream fluffy solid (65 mg, 52% over three steps). ¹H NMR(400 MHz, d₄-MeOD) δ 7.75 (s, 1H), 7.52-7.43 (m, 1H), 7.21-7.10 (m, 2H),4.78-4.67 (m, 1H), 3.37-3.22 (m, 4H), 3.18-3.08 (m, 1H), 2.08-1.88 (m,3H), 1.87-1.63 (m, 3H), 1.46 (d, J=4.2 Hz, 3H), 1.45 (d, J=4.2 Hz, 3H).LCMS (ES+) m/z 476 (M+1)

Example 311(R)-5-Amino-N-(5-(4-aminoazepan-1-yl)-1-cyclopropyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide311

Following the procedure for Example 241 starting with (R)-tert-butyl2-(2-fluorophenyl)-4-(1-cyclopropyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamategave 311 as a cream solid (90 mg, 90%). ¹H-NMR (400 MHz, d₄-MeOD) δ 7.62(s, 1H), 7.53-7.43 (m, 1H), 7.21-7.11 (m, 2H), 3.55-3.49 (m, 1H),3.36-3.32 (m, 4H), 3.20-3.09 (m, 1H), 2.09-1.89 (m, 3H), 1.90-1.64 (m,3H), 1.18-1.03 (m, 4H). LCMS (ES+) m/z 474.0 (M+1).

Example 312(R)-5-Amino-N-(5-(4-aminoazepan-1-yl)-1-cyclopropylmethyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide312

Following the procedure for Example 241 starting with (R)-tert-butyl2-(2-fluorophenyl)-4-(1-cyclopropylmethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamategave 312 as a cream solid (90 mg, 91%). ¹H-NMR (400 MHz, d₄-MeOD) δ7.76-7.70 (s, 1H), 7.53-7.43 (m, 1H), 7.21-7.10 (m, 2H), 3.92 (d, J=7Hz, 2H), 3.33-3.21 (m, 4H), 3.16-3.05 (m, 1H), 2.06-1.86 (m, 3H),1.86-1.61 (m, 3H), 1.38-1.24 (m, 1H), 0.63-0.56 (m, 2H), 0.49-0.39 (m,2H). LCMS (ES+) m/z 488.0 (M+1).

Example 313(S)-5-Amino-N-(5-(4-aminoazepan-1-yl)-1-ethyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide313

Following the procedure for Example 241 starting with (S)-tert-butyl2-(2-fluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamategave 313 as a pale yellow solid (90 mg, 85%). ¹H-NMR (400 MHz, d₄-MeOD)δ 7.71 (s, 1H), 7.52-7.43 (m, 1H), 7.20-7.11 (m, 2H), 4.10 (q, J=7 Hz,2H), 3.32-3.17 (m, 4H), 3.16-3.05 (m, 1H), 2.06-1.86 (m, 3H), 1.86-1.62(m, 3H), 1.47-1.38 (t, J=7 Hz, 3H). LCMS (ES+) m/z 462.0 (M+1).

Example 3145-Amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-chloro-2-fluorophenyl)thiazole-4-carboxamide314

Following the procedure for Example 278 starting with tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateand 5-chloro-2-fluorophenylboronic acid gave 314 as a grey solid (29.2mg, 31%). ¹H NMR (400 MHz, d₄-MeOD) δ 8.34 (dd, J=6.4, 2.7 Hz, 1H), 7.47(s, 1H), 7.43-7.37 (m, 1H), 7.27 (dd, J=10.9, 8.8 Hz, 1H), 3.74 (s, 3H),3.27-3.11 (m, 4H), 2.63 (d, J=6.6 Hz, 2H), 1.86 (d, J=12.6 Hz, 2H),1.56-1.47 (m, 1H), 1.38 (qd, J=11.9, 4.4 Hz, 2H). LCMS (ES+) m/z 480(M+1).

Example 315(S)-5-amino-2-(3-(3-(aminomethyl)pyrrolidin-1-yl)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide315 Step 1: (S)-tert-Butyl2-(3-(3-(butyloxycarbonylaminomethyl)pyrrolidin-1-yl)phenyl)-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

Following the procedure for Example 273 starting with 1,3-dibromobenzeneand (R)-tert-butyl pyrrolidin-3-ylmethylcarbamate and tert-butyl2-bromo-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate gave(S)-tert-butyl2-(3-(3-(butyloxycarbonylaminomethyl)pyrrolidin-1-yl)phenyl)-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateas a yellow gum (71 mg, 16%). LCMS (ES+) m/z 598 (M+1)

Step 2: Acidic deprotection of (S)-tert-butyl2-(3-(3-(butyloxycarbonylaminomethyl)pyrrolidin-1-yl)phenyl)-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamategave the mono-formate salt of 315 as a pale brown solid (30 mg, 65%). ¹HNMR (400 MHz, d₆-DMSO with D₂O) δ 8.40 (s, 1H), 7.96 (s, 1H), 7.63 (s,1H), 7.24 (t, J=7.9 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H), 6.98 (s, 1H), 6.57(d, J=7.9 Hz, 1H), 3.79 (s, 3H), 3.47 (t, J=8.6 Hz, 1H), 3.43-3.35 (m,1H), 3.34-3.27 (m, 1H), 3.07 (dd, J=9.8, 6.9 Hz, 1H), 2.86 (d, J=7.3 Hz,2H), 2.55-2.48 (m, 1H), 2.19-2.13 (m, 1H), 1.79-1.73 (m, 1H). LCMS (ES+)m/z 398 (M+1)

Example 3165-amino-2-(3-(3-aminopyrrolidin-1-yl)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide316 Step 1: tert-Butyl 2-(3-(3-(butyloxycarbonylaminopyrrolidin-1-yl)phenyl)-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

Following the procedure for Example 273 starting with 1,3-dibromobenzeneand tert-butyl pyrrolidin-3-ylcarbamate and tert-butyl2-bromo-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate gavetert-butyl 2-(3-(3-(butyloxycarbonylaminopyrrolidin-1-yl)phenyl)-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateas a yellow gum (105 mg, 22%). LCMS (ES+) m/z 584 (M+1)

Step 2: Acidic deprotection of tert-butyl 2-(3-(3-(butyloxycarbonylaminopyrrolidin-1-yl)phenyl)-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamategave 316 as an off-white solid (38 mg, 55%). ¹H NMR (400 MHz, d₆-DMSO) δ7.93 (s, 1H), 7.62 (s, 1H), 7.22 (t, J=7.9 Hz, 1H), 7.01 (d, J=7.9 Hz,1H), 6.95 (s, 1H), 6.54 (dd, J=7.9, 2.4 Hz, 1H), 3.78 (s, 3H), 3.55-3.49(m, 1H), 3.46 (dd, J=9.5, 6.4 Hz, 1H), 3.41-3.35 (m, 1H), 3.28-3.23 (m,1H), 2.94 (dd, J=9.4, 5.1 Hz, 1H), 2.14-2.09 (m, 1H), 1.77-1.71 (m, 1H).Exchangeable protons not visible. LCMS (ES+) m/z 384 (M+1)

Example 317 3-amino-6-bromo-N-(1-methyl-1H-pyrazol-4-yl)picolinamide 317

1-Methyl-4-nitro-1H-pyrazole (1.62 g, 12.7 mmol) was dissolved inmethanol (250 mL) and hydrogenated on H-Cube at 60 bar hydrogen pressureand 70° C. to give 1-methyl-1H-pyrazol-4-amine (1.23 g, 99%).

To a 100 mL round bottom flask containing 1-methyl-1H-pyrazol-4-amine(700 mg, 7.0 mmol), 3-amino-6-bromopicolinic acid (1.86 g, 8.5 mmol) andPyBop (4.12 g, 8.0 mmol) was added methylene chloride (30 mL) anddiisopropylethylamine (3.8 mL, 21.6 mmol). The reaction mixture wasstirred for 24 hr at room temperature and the reaction was monitored byLCMS. Upon completion of the reaction, the solvent was distilled off andthe crude material was purified via flash chromatography, heptane/ethylacetate 0% to 100% to afford a yellow solid. A fraction of it waspurified via reverse phase HPLC to afford 317. ¹H NMR (400 MHz, DMSO) δ10.25 (s, 1H), 8.03 (s, 1H), 7.70 (s, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.19(d, J=8.7 Hz, 1H), 7.02 (br, 2H), 3.81 (s, 3H). MS (ESI) m/z:296.0/298.0 [M+H⁺].

Example 3183-amino-N-(1-methyl-1H-pyrazol-4-yl)-6-(3-(piperidin-1-yl)phenyl)picolinamide318

To a microwave reaction vial was added 317 from Example 317 (150 mg,0.51 mmol), 3-(piperidin-1-yl)phenylboronic acid (312 mg, 1.52 mmol),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (41 mg,0.051 mmol), a 1M solution of Na₂CO₃ (0.76 mL), a 1M solution ofpotassium acetate (0.76 mL) and acetonitrile (11 mL). The mixture wasirradiated to 120° C. with a microwave for 30 min and cooled to roomtemperature. It was filtered through Celite and thoroughly washed withmethylene chloride. The filtrate was concentrated and the residue waspurified via flash chromatography, 0 to 7% methanol in methylenechloride (with 1% ammonium hydroxide). The product was further purifiedvia reverse phase HPLC to afford 318. ¹H NMR (400 MHz, DMSO) δ 10.34 (s,1H), 8.07 (s, 1H), 7.86 (d, J=8.7 Hz, 1H), 7.71 (s, 1H), 7.59-7.43 (m,2H), 7.34-7.17 (m, 2H), 7.03-6.84 (m, 3H), 3.83 (s, 3H), 3.26-3.18 (m,4H), 1.73-1.48 (m, 7H). MS (ESI) m/z: 377.2 [M+H⁺].

Example 3195-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(1,4-oxazepan-4-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide319 Step 1: 4-(1-Methyl-4-nitro-1H-pyrazol-5-yl)-1,4-oxazepane

Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 1,4-oxazepane gave4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-oxazepane as a yellow oil (72mg, 52%). ¹H NMR (400 MHz, CDCl₃) δ 8.03 (s, 1H), 3.94 (t, J=5.6 Hz,2H), 3.88-3.84 (m, 2H), 3.80 (s, 3H), 3.40-3.35 (m, 4H), 2.07-1.99 (m,2H)

Step 2: Following the procedure for Example 243 starting with4-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-oxazepane gave 319 as a beigesolid (53 mg, 45% over three steps). ¹H NMR (400 MHz, CDCl₃) δ 8.67 (s,1H), 7.85 (s, 1H), 7.38-7.23 (m, 1H), 7.03 (t, J=8.8 Hz, 2H), 6.14 (s,2H), 3.96 (t, J=5.7 Hz, 2H), 3.83 (t, J=4.5 Hz, 2H), 3.76 (s, 3H), 3.35(t, J=6.0 Hz, 4H), 2.05-1.96 (m, 2H). LCMS (ES+) m/z 435 (M+1)

Example 3205-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(5-oxo-1,4-diazepan-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide320 Step 1: 1-(1-Methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepan-5-one

Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and 1,4-diazepan-5-onegave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepan-5-one as a yellowoil (173 mg, 58%). ¹H NMR (400 MHz, CDCl₃) δ 8.03 (s, 1H), 6.35 (s, 1H),3.82 (s, 3H), 3.53-3.47 (m, 2H), 3.38-3.31 (m, 4H), 2.83-2.78 (m, 2H)

Step 2: Following the procedure for Example 243 starting with1-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,4-diazepan-5-one gave 320 as awhite solid (98 mg, 26% over three steps). ¹H NMR (400 MHz, d₆-DMSO) δ8.82 (s, 1H), 7.65 (t, J=5.5 Hz, 1H), 7.60-7.47 (m, 3H), 7.41 (s, 1H),7.31-7.24 (m, 2H), 3.67 (s, 3H), 3.27-3.21 (m, 2H), 3.18-3.10 (m, 5H),2.57-2.48 (m, 1H). LCMS (ES+) m/z 448 (M+1)

Example 3215-amino-2-(2,6-difluorophenyl)-N-(5-(4-(2-hydroxyethyl)piperazin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide321 Step 1:2-(4-(1-Methyl-4-nitro-1H-pyrazol-5-yl)piperazin-1-yl)ethanol

Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and2-(piperazin-1-yl)ethanol gave2-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperazin-1-yl)ethanol as a creamsolid (0.30 g, 95%). ¹H NMR (400 MHz, CDCl₃) δ 8.03 (s, 1H), 3.78 (s,3H), 3.67 (t, J=5.3 Hz, 2H), 3.26 (t, J=4.6 Hz, 4H), 2.72-2.62 (m, 6H).OH not seen

Step 2: Following the procedure for Example 243 starting with2-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperazin-1-yl)ethanol gave 321as a light peach solid (165 mg, 67% over three steps). ¹H NMR (400 MHz,CDCl₃) δ 8.61 (s, 1H), 7.82 (s, 1H), 7.35-7.29 (m, 1H), 7.08-7.01 (m,2H), 6.12 (s, 2H), 3.74 (s, 3H), 3.65 (t, J=5.3 Hz, 2H), 3.21 (t, J=4.5Hz, 4H), 2.69-2.60 (m, 6H). OH not seen. LCMS (ES+) m/z 464 (M+1)

Example 322(S)-5-amino-2-(3-(3-hydroxypyrrolidin-1-yl)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide322 Step 1: (S)-tert-butyl2-(3-(3-hydroxypyrrolidin-1-yl)phenyl)-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

Following the procedure for Example 273 starting with 1,3-dibromobenzeneand (S)-pyrrolidin-3-ol and tert-butyl2-bromo-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate gave(S)-tert-butyl2-(3-(3-hydroxypyrrolidin-1-yl)phenyl)-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateas a yellow solid (110 mg, 40%). LCMS (ES+) m/z 485 (M+1)

Step 2: Acidic deprotection of (S)-tert-butyl2-(3-(3-hydroxypyrrolidin-1-yl)phenyl)-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamategave 322 as an off-white solid (25 mg, 29%). ¹H NMR (400 MHz, d₆-DMSOwith D₂O) δ 7.95 (s, 1H), 7.62 (s, 1H), 7.22 (t, J=7.9 Hz, 1H), 7.01 (d,J=7.7 Hz, 1H), 6.96 (s, 1H), 6.55 (dd, J=8.3, 2.3 Hz, 1H), 4.42 (s, 1H),3.78 (s, 3H), 3.45 (dd, J=10.4, 4.8 Hz, 1H), 3.42-3.26 (m, 2H), 3.13 (d,J=10.4 Hz, 1H), 2.10-1.99 (m, 1H), 1.94-1.87 (m, 1H). LCMS (ES+) m/z 385(M+1)

Example 323(R)-5-Amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(4-methoxy-2-(trifluoromethyl)phenyl)thiazole-4-carboxamide323

A mixture of (R)-benzyl1-(4-(5-tert-butoxycarbonyl-amino-2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate(130 mg, 0.20 mmol), Na₂CO₃ (42 mg, 0.40 mmol) and4-methoxy-2-(trifluoromethyl)phenylboronic acid (70 mg, 0.32 mmol) inDME (1.5 mL) and water (0.5 mL) was degassed by gently bubbling nitrogenthrough the mixture for 15 min.[1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (16 mg,0.020 mmol) was then added and the mixture degassed for a further 10 minbefore being heated in a microwave at 130° C. for 35 min. The solventswere removed under reduced pressure and the residue purified via silicagel column chromatography (0-100% EtOAc/isohexane). The isolatedintermediate was dissolved in DCM (2 mL) and a 1M solution of borontribromide in DCM (0.6 mL, 0.60 mmol) was added. The mixture was stirredat room temperature for 6 hr. The mixture was concentrated under reducedpressure and the residue purified by preparative HPLC to yield 323 as abrown solid (23 mg, 22%). ¹H NMR (400 MHz, d₆-DMSO) δ 8.53 (s, 1H), 7.71(d, J=8.6 Hz, 1H), 7.60 (s, 1H), 7.42-7.29 (m, 4H), 3.90 (s, 3H), 3.65(s, 3H), 3.13-3.04 (m, 4H), 3.01-2.91 (m, 1H), 1.86-1.75 (m, 3H),1.64-1.46 (m, 3H). LCMS (ES+) m/z 510 (M+1).

Example 324(R)-5-Amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-fluorophenyl)thiazole-4-carboxamide324

Following the procedure for Example 323 starting with (R)-benzyl1-(4-(5-tert-butoxycarbonyl-amino-2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamateand 3-fluorophenylboronic acid gave 324 as a pale brown solid (26 mg,29%). ¹H NMR (400 MHz, d₆-DMSO) δ 8.91 (s, 1H), 7.73 (d, J=10.3 Hz, 1H),7.62 (d, J=7.8 Hz, 1H), 7.55-7.47 (m, 4H), 7.24 (td, J=7.8, 2.6 Hz, 1H),3.66 (s, 3H), 3.24-3.02 (m, 5H), 1.88-1.79 (m, 3H), 1.64-1.46 (m, 3H).LCMS (ES+) m/z 430 (M+1).

Example 3253-amino-N-(1-methyl-1H-pyrazol-4-yl)-6-(3-morpholinophenyl)picolinamide325

Following the procedures described in Example 318, 325 was obtained. ¹HNMR (400 MHz, DMSO) δ 10.35 (s, 1H), 8.07 (s, 1H), 7.88 (d, J=8.8 Hz,1H), 7.72 (s, 1H), 7.59 (d, J=12.1 Hz, 2H), 7.35-7.21 (m, 2H), 6.94 (d,J=5.3 Hz, 3H), 3.83 (s, 3H), 3.80-3.69 (m, 4H), 3.25-3.12 (m, 4H). MS(ESI) m/z: 379.2 [M+H⁺].

Example 326(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)pyrimidine-4-carboxamide326 Step 1: ethyl 5-amino-2-chloropyrimidine-4-carboxylate

In a Parr hydrogenator, ethyl2,6-dichloro-5-nitropyrimidine-4-carboxylate (2.16 g, 8.12 mmol), 10%Pd/C (2.0 g, 0.94 mmol), magnesium monoxide (1.60 g, 39.7 mmol) and1,4-dioxane (100 mL) were charged. The hydrogenation was allowed to goat room temperature under 50-60 psi for 2 days while monitored by LCMS.The reaction mixture was filtered through Celite and washed withmethanol. The filtrate was concentrated and purified via flashchromatography eluting with 50 to 100% ethyl acetate in heptane to giveethyl 5-amino-2-chloropyrimidine-4-carboxylate (0.90 g, 55%).

Step 2: 5-amino-2-chloropyrimidine-4-carboxylic acid

Ethyl 5-amino-2-chloropyrimidine-4-carboxylate (0.90 g, 4.0 mmol) wasdissolved in THF (22 mL). To it water (8 mL) and 1M lithium hydroxide(11 mL, 11 mmol) were added and the mixture was stirred at roomtemperature for 6 h. The reaction was then acidified to pH6 with 6N HCl(1.15 mL) and concentrated in vacuo to remove organic solvent. The solidwas collected by filtration and washed with water to give5-amino-2-chloropyrimidine-4-carboxylic acid as a yellow solid (434 mg,60%).

Step 3: (R)-benzyl1-(4-(5-amino-2-chloropyrimidine-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate

Following the procedure from Example 140, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16and 5-amino-2-chloropyrimidine-4-carboxylic acid were converted to(R)-benzyl1-(4-(5-amino-2-chloropyrimidine-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate.

Step 4: In a 40 mL sealed vial was added (R)-benzyl1-(4-(5-amino-2-chloropyrimidine-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate(140 mg, 0.28 mmol), 1,4-cyclohexadiene (0.16 mL, 1.68 mmol) and ethanol(12 mL). 10% Pd/C (30 mg, 0.028 mmol) was added and the reaction vialwas vacuum purged with nitrogen three times. The reaction mixture wasthen stirred at 95° C. under nitrogen for 2 h. LCMS indicatedde-chlorinated product as the malor product. After cooling down to roomtemperature, the reaction mixture was filtered through Celite and rinsedthoroughly with methanol. The solvent was distilled off under reducedpressure to give the crude product which was purified via reverse phaseHPLC to afford 326. ¹H NMR (400 MHz, DMSO) δ 8.48 (s, 1H), 8.46 (s, 1H),7.51 (s, 1H), 6.88 (s, 3H), 3.65 (s, 4H), 3.19-2.89 (m, 9H), 1.93-1.69(m, 4H), 1.69-1.41 (m, 4H). MS (ESI) m/z: 331.2 [M+H⁺].

Example 327(R)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(4-(methylamino)azepan-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide327

Following procedures as in Example 141,5-(tert-butoxy-carbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid was converted to 327: ¹H-NMR (DMSO, 500 MHz) δ (ppm): 8.79 (s, 1H),7.51 (m, 4H), 7.26 (t, 8.5 Hz, 2H), 3.64 (s, 3H), 3.18 (m, 1H), 3.10 (m,3H), 2.81 (s, 1H), 2.30 (s, 3H), 1.92-1.90 (m, 3H), 1.57 (m, 3H); MS(ESI) m/z: 462 [M+H⁺]

Example 328(S)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(4-(methylamino)azepan-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide328

Following procedures as in Example 141,5-(tert-butoxy-carbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid was converted to 328: ¹H-NMR (DMSO, 500 MHz) δ (ppm): 8.77 (s, 1H),7.51 (m, 4H), 7.27 (t, 8.5 Hz, 2H), 3.64 (s, 3H), 3.21 (m, 1H), 3.17 (m,3H), 2.81 (s, 1H), 2.30 (s, 3H), 1.92-1.90 (m, 3H), 1.60 (m, 3H); MS(ESI) m/z: 462 [M+H⁺]

Example 3293-amino-N-(1-methyl-1H-pyrazol-4-yl)-6-(3-(pyrrolidin-1-yl)phenyl)picolinamide329

Following the procedures described in Example 318, 329 was obtained. ¹HNMR (400 MHz, DMSO) δ 10.32 (s, 1H), 8.07 (s, 1H), 7.83 (d, J=8.7 Hz,1H), 7.73 (s, 1H), 7.38-7.18 (m, 3H), 7.16 (s, 1H), 6.92 (s, 2H), 6.55(d, J=8.0 Hz, 1H), 3.83 (s, 3H), 3.33 (t, J=6.3 Hz, 4H), 1.98 (t, J=6.4Hz, 4H). MS (ESI) m/z: 363.1 [M+H⁺].

Example 330(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)pyrimidine-4-carboxamide330

Following the procedure from Example 326, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16was converted to (R)-benzyl1-(4-(5-amino-2-chloropyrimidine-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate.

Following the procedure from Example 229, (R)-benzyl1-(4-(5-amino-2-chloropyrimidine-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamatewas converted to 330. ¹H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 8.07 (td,J=8.1, 1.7 Hz, 1H), 7.72 (s, 1H), 7.55-7.39 (m, 1H), 7.32 (dd, J=14.1,7.3 Hz, 2H), 7.07 (br, 2H), 3.67 (s, 3H), 3.20-3.06 (m, 4H), 3.03-2.89(m, 1H), 1.89-1.72 (m, 3H), 1.70-1.42 (m, 3H). MS (ESI) m/z: 425.1[M+H⁺].

Example 3313-amino-N-(1-methyl-1H-pyrazol-4-yl)-6-(3-(piperazin-1-yl)phenyl)picolinamide331

tert-Butyl4-(3-(5-amino-6-(1-methyl-1H-pyrazol-4-ylcarbamoyl)pyridin-2-yl)phenyl)piperazine-1-carboxylatewas prepared following the procedures described in Example 318, andtreated with 4M HCl in dioxane at room temperature to give 331, purifiedby reverse phase HPLC. ¹H NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 8.07 (s,1H), 7.86 (d, J=8.8 Hz, 1H), 7.72 (s, 1H), 7.54 (d, J=7.2 Hz, 2H),7.34-7.18 (m, 2H), 6.92 (d, J=12.1 Hz, 3H), 3.83 (s, 3H), 3.20-3.06 (m,4H), 2.93-2.79 (m, 4H). MS (ESI) m/z: 378.1 [M+H⁺].

Example 332(R)-5-amino-N-(5-(azepan-4-ylamino)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide332 Step 1: (R)-tert-Butyl4-(1-methyl-4-nitro-1H-pyrazol-5-ylamino)azepane-1-carboxylate

A solution of (R)-tert-butyl4-(benzyloxycarbonylamino)azepane-1-carboxylate from Examples 63 and 83(3.25 g, 9.85 mmol) in MeOH (100 mL) was stirred at room temperatureunder an atmospheric pressure of hydrogen gas in the presence of 10%Pd/C (1 g) for 1.5 hr. The mixture was filtered through celite and thesolvent removed under reduced pressure to afford (R)-tert-butyl4-(2,2,2-trifluoroacetamido)azepane-1-carboxylate as a pale grey oil (2g, 100%). A solution of this oil (0.145 g, 0.68 mmol) in ethanol (3 mL)was added to 5-chloro-1-methyl-4-nitro-1H-pyrazole (0.1 g, 0.62 mmol).DIPEA (1 mL) was added and the reaction mixture was heated at 130° C. inthe microwave for 1 hr followed by a further 3×90 min at 140° C. Thesolvent was removed under reduced pressure and the crude material waspurified via silica gel chromatography (60% EtOAc/isohexane) to afford(R)-tert-butyl4-(1-methyl-4-nitro-1H-pyrazol-5-ylamino)azepane-1-carboxylate as ayellow oil (148 mg, 71%). ¹H NMR (400 MHz, CDCl₃) δ 7.90 (s, 1H),6.60-6.50 (m, 1H), 3.80 (s, 3H), 3.79-3.67 (m, 1H), 3.60-3.52 (m, 1H),3.49-3.44 (m, 1H), 3.44-3.22 (m, 2H), 2.25-2.10 (m, 1H), 2.05-1.62 (m,5H), 1.48 (s, 9H)

Step 2: Following the procedure for Example 243 starting with(R)-tert-butyl4-(1-methyl-4-nitro-1H-pyrazol-5-ylamino)azepane-1-carboxylate gave 332as an orange foam (107 mg, 65% over three steps). ¹H NMR (400 MHz,CDCl₃) δ 8.49 (s, 1H), 7.54 (s, 1H), 7.37-7.30 (m, 1H), 7.06-6.98 (m,2H), 6.16 (s, 2H), 3.90 (d, J=8.9 Hz, 1H), 3.73 (s, 3H), 3.29-3.22 (m,1H), 3.03-2.69 (m, 4H), 2.01-1.46 (m, 6H). Alkyl NH not seen. LCMS (ES+)m/z 448 (M+1)

Example 3335-amino-2-(2,6-difluorophenyl)-N-(1-(2-(piperidin-4-yl)ethyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)thiazole-4-carboxamide333 Step 1: tert-Butyl4-(2-(7-nitro-2,3-dihydro-1H-pyrazolo[1,5-c]imidazol-1-yl)ethyl)piperidine-1-carboxylate

Sodium hydride (60% dispersion in mineral oil, 39 mg, 0.97 mmol) wasadded portionwise to a stirred solution of7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazole (0.125 g, 0.81 mmol) inanhydrous THF (10 mL) at room temperature under a nitrogen atmosphere.The mixture was stirred for 10 min. before a solution of tert-butyl4-(2-(tosyloxy)ethyl)piperidine-1-carboxylate (0.31 g, 0.81 mmol) in THF(5 mL) was added portionwise over 10 min. The reaction was stirred for 6hr at room temperature followed by 18 hr at 50° C. Further sodiumhydride (60% dispersion in mineral oil, 39 mg, 0.97 mmol) was added andstirring continued at 60° C. for a further 24 h. The reaction was cooledand water was added dropwise. The mixture was extracted with EtOAc andthe combined organics were dried over MgSO₄ and concentrated underreduced pressure. The crude residue was purified via silica gelchromatography (0-100% EtOAc/isohexane) to give tert-butyl4-(2-(7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazol-1-yl)ethyl)piperidine-1-carboxylateas a yellow oil (50 mg, 17%). ¹H NMR (400 MHz, CDCl₃) δ 7.83 (s, 1H),4.24-4.16 (m, 2H), 4.25-3.97 (m, 2H), 3.83-3.77 (s, 2H), 3.27 (s, 2H),3.22 (t, J=6.8 Hz, 2H), 2.72-2.62 (s, 2H), 1.73-1.65 (m, 3H), 1.46-1.44(m, 9H) 1.40-1.05 (m, 2H)

Step 2: Following the procedure for Example 230 starting with tert-butyl4-(2-(7-nitro-2,3-dihydro-1H-pyrazolo[1,5-c]imidazol-1-yl)ethyl)piperidine-1-carboxylategave 333 as a cream solid (13 mg, 20% over three steps). ¹H NMR (400MHz, d₄-MeOD) δ 7.54-7.45 (m, 1H), 7.33 (s, 1H), 7.22-7.12 (m, 2H),4.18-4.08 (m, 2H), 3.85-3.72 (m, 2H), 3.30-3.12 (m, 4H), 2.95-2.82 (m,2H), 1.93 (d, J=14.0 Hz, 2H), 1.81-1.69 (m, 1H), 1.59 (dd, J=14.0, 6.9Hz, 2H), 1.42-1.27 (m, 2H). LCMS (ES+) m/z 474 (M+1)

Example 3345-amino-2-(2,6-difluorophenyl)-N-(5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide334 Step 1: (3aR,6aS)-tert-Butyl5-(1-methyl-4-nitro-1H-pyrazol-5-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and(3aR,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylategave (3aR,6aS)-tert-butyl5-(1-methyl-4-nitro-1H-pyrazol-5-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylateas a yellow oil (0.36 g, 86%). ¹H NMR (400 MHz, CDCl₃) δ 8.05 (s, 1H),3.75 (s, 3H), 3.73-3.55 (m, 4H), 3.42-3.33 (m, 2H), 3.17-3.04 (m, 4H),1.48 (s, 9H)

Step 2: Following the procedure for Example 243 starting with(3aR,6aS)-tert-butyl5-(1-methyl-4-nitro-1H-pyrazol-5-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylategave 334 as the mono-formate salt as an off-white solid (52 mg, 37%). ¹HNMR (400 MHz, d₆-DMSO) δ 8.84 (s, 1H), 8.37 (s, 1H), 7.61-7.46 (m, 3H),7.37 (s, 1H), 7.32-7.23 (m, 2H), 3.65 (s, 3H), 3.34-3.26 (m, 2H),3.21-3.18 (m, 2H), 3.00 (d, J=9.3 Hz, 2H), 2.79-2.69 (m, 4H). Alkyl NHnot seen. LCMS (ES+) m/z 446 (M+1)

Example 3355-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(methyl(piperidin-4-yl)amino)-1H-pyrazol-4-yl)thiazole-4-carboxamide335 Step 1: tert-Butyl4-(methyl(1-methyl-4-nitro-1H-pyrazol-5-yl)amino)piperidine-1-carboxylate

Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and tert-butyl4-(methylamino)piperidine-1-carboxylate gave tert-butyl4-(methyl(1-methyl-4-nitro-1H-pyrazol-5-yl)amino)piperidine-1-carboxylate(75 mg, 36%). ¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 4.15-4.05 (m, 2H),3.75 (s, 3H), 3.32 (tt, J=11.1, 3.9 Hz, 1H), 2.81 (s, 3H), 2.72 (t,J=12.9 Hz, 2H), 1.79-1.70 (m, 2H), 1.48 (s, 9H), 1.40-1.25 (m, 2H)

Step 2: Following the procedure for Example 243 starting with tert-butyl4-(methyl(1-methyl-4-nitro-1H-pyrazol-5-yl)amino)piperidine-1-carboxylategave 335 as a yellow solid (45 mg, 55% over three steps). ¹H NMR (400MHz, CDCl₃) δ 8.60 (s, 1H), 7.97 (s, 1H), 7.35-7.28 (m, 1H), 7.02 (t,J=8.9 Hz, 2H), 6.11 (s, 2H), 3.73 (s, 3H), 3.12 (d, J=12.4 Hz, 2H),3.05-3.01 (m, 1H), 2.85 (s, 3H), 2.68-2.58 (m, 2H), 1.89-1.82 (m, 2H),1.55-1.42 (m, 2H). Alkyl NH not seen. LCMS (ES+) m/z 448 (M+1)

Example 336(R)-5-Amino-N-(5-(4-aminoazepan-1-yl)-1-ethyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide336

Following the procedure for Example 241 starting with (R)-tert-butyl2-(2-fluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamategave, after preparative HPLC, 336 as a cream solid (31 mg, 30%). ¹H-NMR(400 MHz, d₄-MeOD) δ 7.69 (s, 1H), 7.50-7.40 (m, 1H), 7.19-7.09 (m, 2H),4.08 (q, J=7 Hz, 2H), 3.30-3.16 (m, 4H), 3.14-3.05 (m, 1H), 2.05-1.84(m, 3H), 1.83-1.61 (m, 3H), 1.44-1.35 (m, 3H). LCMS (ES+) m/z 462.0(M+1).

Example 337(R)-5-Amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cyclopentenylthiazole-4-carboxamide337

Following the procedure for Example 350 starting with (R)-tert-butyl2-bromo-4-(1-methyl-5-(4-(2,2,2-trifluoroacetamido)-azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateand cyclopent-1-ene-1-boronic acid gave 397 as an orange solid (8 mg,14%). ¹H NMR (400 MHz, d₄-MeOD) δ 7.48 (s, 1H), 6.13 (t, J=2.5 Hz, 1H),3.67 (s, 3H), 3.22-3.17 (m, 3H), 3.10-3.03 (m, 1H), 2.77-2.70 (m, 2H),2.53-2.47 (m, 2H), 2.03-1.81 (m, 6H), 1.73-1.58 (m, 3H). LCMS (ES+) m/z402 (M+1).

Example 338(R)-5-Amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cyclohexenylthiazole-4-carboxamide338

Following the procedure for Example 350 starting with (R)-tert-butyl2-bromo-4-(1-methyl-5-(4-(2,2,2-trifluoroacetamido)-azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateand cyclohex-1-ene-1-boronic acid gave 338 as a white solid (17.1 mg,33%). ¹H NMR (400 MHz, d₄-MeOD) δ 7.58 (s, 1H), 6.31 (t, J=4.1 Hz, 1H),3.74 (s, 3H), 3.30-3.24 (m, 3H), 3.13-3.07 (m, 1H), 2.64-2.45 (m, 2H),2.28-2.24 (m, 2H), 2.04-1.88 (m, 3H), 1.83-1.66 (m, 8H). LCMS (ES+) m/z416 (M+1).

Example 339(R,E)-5-Amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cycloheptenylthiazole-4-carboxamide339

Following the procedure for Example 350 starting with (R)-tert-butyl2-bromo-4-(1-methyl-5-(4-(2,2,2-trifluoroacetamido)-azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamateand 1-cycloheptenylboronic acid pinacol ester gave 339 as an orangesolid (7.0 mg, 14%). ¹H NMR (400 MHz, d₄-MeOD) δ 7.57 (s, 1H), 6.46 (t,J=6.7 Hz, 1H), 3.74 (s, 3H), 3.31-3.22 (m, 4H), 3.14-3.06 (m, 1H),2.88-2.82 (m, 2H), 2.39-2.32 (m, 2H), 2.05-1.56 (m, 12H). LCMS (ES+) m/z430 (M+1)

Example 3405-amino-N-(5-((cis-4-aminocyclohexylamino)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide340

Following the procedures from Example 2, tert-butylcis-4-(4-amino-1-methyl-1H-pyrazol-5-ylamino)cyclohexylcarbamate wasprepared.

Following the procedures from Example 140, tert-butyl(cis-4-(4-amino-1-methyl-1H-pyrazol-5-ylamino)cyclohexylcarbamate wasconverted to 340. ¹H NMR (400 MHz, DMSO) δ 8.89 (s, 1H), 7.59-7.38 (m,4H), 7.26 (t, J=8.6 Hz, 2H), 4.58 (d, J=7.4 Hz, 1H), 3.61 (s, 3H), 2.97(br, 1H), 2.76 (br, 1H), 1.53 (dt, J=17.3, 7.0 Hz, 9H). MS (ESI) m/z:448.2 [M+H⁺].

Example 341(S)-3-amino-6-(3-(3-aminopiperidin-1-yl)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)picolinamide341 Step 1: (S)-tert-butyl1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-3-ylcarbamate

A solution of tert-butyl N-[(3S)-3-piperidyl]carbamate (533 mg, 2.66mmol), 1,3-dibromobenzene (878 mg, 3.72 mmol), (+/−)-BINAP (171 mg,0.266 mmol), Pd₂(dba)₃ (122 mg, 0.133 mmol) and sodium tert-butoxide(277 mg, 2.79 mmol) in toluene (25 mL) was heated at 85° C. overnight.The reaction mixture was filtered through Celite and washed thoroughlywith EA. The crude product was purified via flash chromatography elutedwith 0 to 100% ethyl acetate in heptane to give (S)-tert-butyl1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-3-ylcarbamate.

Step 2: Following the procedure from Example 331,3-amino-6-bromo-N-(1-methyl-1H-pyrazol-4-yl)picolinamide was convertedto 341. ¹H NMR (400 MHz, DMSO) δ 10.34 (s, 1H), 8.08 (s, 1H), 7.85 (d,J=8.7 Hz, 1H), 7.72 (s, 1H), 7.56 (s, 1H), 7.51 (d, J=7.7 Hz, 1H), 7.28(t, J=8.4 Hz, 2H), 7.01-6.80 (m, 3H), 3.83 (s, 3H), 3.72 (d, J=9.2 Hz,1H), 3.63 (d, J=12.2 Hz, 1H), 2.89-2.77 (m, 1H), 2.77-2.63 (m, 1H),1.90-1.83 (m, 1H), 1.80-1.72 (m, 1H), 1.65-1.53 (m, 1H), 1.27-1.09 (m,1H). MS (ESI) m/z: 392.2 [M+H⁺].

Example 342(S)-3-amino-6-(3-(3-aminopyrrolidin-1-yl)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)picolinamide342

Following the procedure from Example 341,3-amino-6-bromo-N-(1-methyl-1H-pyrazol-4-yl)picolinamide was convertedto 342. ¹H NMR (400 MHz, DMSO) δ 10.32 (s, 1H), 8.07 (s, 1H), 7.83 (d,J=8.7 Hz, 1H), 7.73 (s, 1H), 7.38-7.17 (m, 3H), 7.11 (s, 1H), 6.92 (s,2H), 6.50 (d, J=8.1 Hz, 1H), 3.83 (s, 3H), 3.66-3.56 (m, 1H), 3.56-3.41(m, 3H), 2.99 (dd, J=9.3, 4.7 Hz, 1H), 2.11 (td, J=12.9, 6.4 Hz, 1H),1.74 (td, J=12.8, 6.6 Hz, 1H). MS (ESI) m/z: 378.2 [M+H⁺].

Example 343(R)-3-amino-6-(3-(3-aminopiperidin-1-yl)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)picolinamide343

Following the procedure from Example 341,3-amino-6-bromo-N-(1-methyl-1H-pyrazol-4-yl)picolinamide was convertedto 343. ¹H NMR (400 MHz, DMSO) δ 10.34 (s, 1H), 8.08 (s, 1H), 7.85 (d,J=8.7 Hz, 1H), 7.72 (s, 1H), 7.60-7.44 (m, 2H), 7.28 (t, J=8.1 Hz, 2H),7.00-6.80 (m, 3H), 3.83 (s, 3H), 3.72 (d, J=11.8 Hz, 1H), 3.63 (d,J=12.0 Hz, 1H), 2.93-2.59 (m, 3H), 1.95-1.69 (m, 2H), 1.65-1.52 (m, 1H),1.31-1.07 (m, 1H). MS (ESI) m/z: 392.2 [M+H⁺].

Example 344(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-methylthiazole-4-carboxamide344

Following procedures from Examples 140, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16was converted to 344. ¹H NMR (400 MHz, DMSO) δ 8.70 (s, 1H), 7.44 (s,1H), 7.03 (s, 2H), 3.62 (s, 4H), 3.18-2.96 (m, 7H), 2.44 (d, J=8.4 Hz,4H), 1.94-1.72 (m, 4H), 1.68-1.42 (m, 4H). MS (ESI) m/z: 350.2 [M+H⁺].

Example 345(R)-3-amino-6-(3-(3-aminopyrrolidin-1-yl)phenyl)-N-(1-methyl-1H-pyrazol-4-yl)picolinamide345

Following the procedure from Example 341,3-amino-6-bromo-N-(1-methyl-1H-pyrazol-4-yl)picolinamide was convertedto Example 345. ¹H NMR (400 MHz, DMSO) δ 10.32 (s, 1H), 8.07 (s, 1H),7.83 (d, J=8.7 Hz, 1H), 7.73 (s, 1H), 7.38-7.15 (m, 3H), 7.11 (s, 1H),6.92 (s, 2H), 6.50 (d, J=7.9 Hz, 1H), 3.83 (s, 3H), 3.64-3.54 (m, 1H),3.54-3.40 (m, 3H), 2.99 (dd, J=9.3, 4.7 Hz, 1H), 2.11 (dt, J=12.5, 6.4Hz, 1H), 1.74 (td, J=12.7, 6.4 Hz, 1H). MS (ESI) m/z: 378.2 [M+H⁺].

Example 3465-amino-N-(5-((cis-3-aminocyclohexylamino)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide346

Following the procedures provided in Example 340, racemic 346 wasobtained. The cis diastereoisomers were isolated via chiral preparativeHPLC. ¹H NMR (400 MHz, DMSO) δ 7.61-7.40 (m, 4H), 7.27 (t, J=8.6 Hz,2H), 4.64 (d, J=7.8 Hz, 1H), 3.60 (s, 3H), 2.87-2.73 (m, 1H), 1.96 (d,J=11.7 Hz, 1H), 1.78 (d, J=11.8 Hz, 1H), 1.65 (t, J=15.1 Hz, 2H),1.21-0.78 (m, 4H). MS (ESI) m/z: 448.2 [M+H⁺].

Example 3475-amino-2-(2,6-difluorophenyl)-N-(5-(4-(2,4-dimethoxybenzylamino)cyclohexyl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide347

Following procedures from Examples 113 and shown in FIG. 5, tert-butyl2-(2,6-di-fluorophenyl)-4-(5-(4-(2,4-dimethoxybenzylamino)cyclohexyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamatewas converted to 347: ¹H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 8.30 (s,1H), 7.53 (s, 1H), 7.45 (m, 3H), 7.20 (m, 2H), 7.06 (d, J=8.3 Hz, 1H),6.42 (d, J=2.1 Hz, 1H), 6.29 (dd, J=8.3, 2.1 Hz, 1H), 3.78 (s, 3H), 3.75(m, 2H), 3.70 (m, 5H), 3.51 (s, 3H), 2.77 (m, 2H), 2.14-2.04 (m, 2H),1.80 (d, J=12.8 Hz, 2H), 1.49 (t, J=14.4 Hz, 2H); MS (ESI) m/z:583[M+H⁺]

Example 3485-amino-2-(2,6-difluorophenyl)-N-(1-(piperidin-4-ylmethyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)thiazole-4-carboxamide348 Step 1: tert-Butyl4-((7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazol-1-yl)methyl)piperidine-1-carboxylate

Following the procedure for Example 333 starting with7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazole and tert-butyl4-(tosyloxymethyl)piperidine-1-carboxylate gave tert-butyl4-((7-nitro-2,3-dihydro-1H-pyrazolo[1,5-c]imidazol-1-yl)methyl)piperidine-1-carboxylateas a pale yellow solid (40 mg, 23%). ¹H NMR (400 MHz, CDCl₃) δ 7.82 (s,1H), 4.26-4.02 (m, 6H), 3.77-3.61 (m, 2H), 2.71 (s, 2H), 1.92-1.67 (m,3H), 1.47-1.45 (m, 9H), 1.32-1.11 (m, 2H)

Step 2: Following the procedure for Example 230 starting with tert-butyl4-((7-nitro-2,3-dihydro-1H-pyrazolo[1,5-c]imidazol-1-yl)methyl)piperidine-1-carboxylategave 348 as the mono-formate salt as an off-white foam (41 mg, 11% overthree steps). ¹H NMR (400 MHz, d₄-MeOD) δ 8.55 (s, 1H), 7.54-7.45 (m,1H), 7.31 (s, 1H), 7.19-7.10 (m, 2H), 4.15 (t, J=7.8 Hz, 2H), 3.86 (t,J=7.8 Hz, 2H), 3.38-3.30 (m, 2H), 3.10-3.00 (m, 2H), 2.88 (td, J=12.8,2.9 Hz, 2H), 2.07-1.89 (m, 3H), 1.45-1.30 (m, 2H). LCMS (ES+) m/z 460(M+1)

Example 3495-amino-N-(5-(3-aminopropylamino)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide349 Step 1: tert-Butyl3-(1-methyl-4-nitro-1H-pyrazol-5-ylamino)propylcarbamate

Following Example 58, reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazoleand tert-butyl 3-aminopropylcarbamate gave tert-butyl3-(1-methyl-4-nitro-1H-pyrazol-5-ylamino)propylcarbamate as a paleyellow gum (1.27 g, 85%). ¹H NMR (400 MHz, CDCl₃) δ 7.88 (s, 1H), 6.75(s br, 1H), 4.67 (s br, 1H), 3.84 (s, 3H), 3.54 (q, J=6.6 Hz, 2H), 3.27(q, J=6.6 Hz, 2H), 1.90-1.79 (m, 2H), 1.44 (s, 9H)

Step 2: Following the procedure for Example 230 starting with tert-butyl3-(1-methyl-4-nitro-1H-pyrazol-5-ylamino)propylcarbamate gave 349 as themono-formate salt as an off-white foam (19 mg, 5% over three steps). ¹HNMR (400 MHz, d₄-MeOD) δ 8.56 (s, 1H), 7.55-7.43 (m, 1H), 7.43 (s, 1H),7.21-7.11 (m, 2H), 3.70 (s, 3H), 3.28-3.21 (m, 2H), 3.06-2.97 (m, 2H),1.93-1.82 (m, 2H). LCMS (ES+) m/z 408 (M+1)

Example 350(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,5-dichlorophenyl)thiazole-4-carboxamide350

A mixture of (R)-tert-butyl2-bromo-4-(1-methyl-5-(4-(2,2,2-trifluoroacetamido)-azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate(122 mg, 0.20 mmol), Na₂CO₃ (42 mg, 0.40 mmol) and2,5-dichlorobenzeneboronic acid (38 mg, 0.20 mmol) in DME (1.5 mL) andwater (0.5 mL) was degassed by gently bubbling nitrogen through themixture for 15 min.[1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (16 mg,0.020 mmol) was added and the mixture degassed for a further 10 minbefore being heated in a microwave at 130° C. for 35 min. Water wasadded and the mixture extracted with EtOAc. The combined organic layerswere passed through a phase separation cartridge and concentrated underreduced pressure. The residue was purified via silica gel columnchromatography (0-100% EtOAc/isohexane). The isolated intermediate wasdissolved in a mixture of DCM (1.5 mL) and TFA (0.5 mL) and stirred atroom temperature for 6 hr. The solvents were removed under reducedpressure and the residue dissolved in a mixture of MeOH/water (3 mL,1:1) and K₂CO₃ (55 mg, 0.40 mmol) added. The mixture was heated at 60°C. for 3 hr. The mixture was concentrated under reduced pressure and theresidue purified by preparative HPLC to yield 350 as a yellow solid (12mg, 29%). ¹H NMR (400 MHz, d₄-MeOD) δ 8.35 (d, J=2.6 Hz, 1H), 7.56 (s,1H), 7.52 (d, J=8.6 Hz, 1H), 7.39 (dd, J=8.6, 2.6 Hz, 1H), 3.76 (s, 3H),3.35-3.31 (m, 4H), 3.11-3.09 (m, 1H), 2.04-1.91 (m, 3H), 1.76-1.67 (m,3H). LCMS (ES+) m/z 480 (M+1).

Example 3515-Amino-N-(5-(5-amino-4,4-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide351

HCl in 1,4-dioxane (4 M, 2 mL) was added to a solution of Example 55 (20mg, 0.03 mmol) in MeOH (0.5 mL). This mixture was stirred at roomtemperature for 18 hr. The solvents were removed under reduced pressureand the crude product re-dissolved in MeOH/water (1:1, 5 mL). K₂CO₃ (0.3g, 7, 2.2 mmol) was added and the mixture heated and stirred at 60° C.for 3 hr before being cooled to room temperature. The mixture wasconcentrated under reduced pressure and the residue purified bypreparative HPLC to yield 351 as a white solid (4 mg, 25%). ¹H NMR (400MHz, CDCl₃) δ 9.02 (s, 1H), 7.88 (s, 1H), 7.37-7.28 (m, 1H), 7.08-6.98(m, 2H), 6.15 (s, 2H), 3.73 (s, 3H), 3.39-3.13 (m, 6H), 2.46-2.34 (m,1H), 2.22-2.03 (m, 2H), 1.99-1.89 (m, 1H), 1.83-1.78 (m, 1H). LCMS (ES+)m/z 484.0 (M+1).

Example 3525-Amino-N-(5-((3-aminopropyl)(methyl)amino)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide352

Following the procedure for Example 287 starting from tert-butyl2-(2,6-difluorophenyl)-4-(5-(tert-butyl-(3-methylamino)propylcarbamoyl-3-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamategave 352 as the monoformate salt as a pale brown solid (134 mg, 73%).¹H-NMR (400 MHz, d₄-MeOD) δ 8.56 (s, 1H), 7.60 (s, 1H), 7.53-7.44 (m,1H), 7.18-7.11 (m, 2H), 3.75 (s, 3H), 3.20 (t, J=7.5 Hz, 2H), 2.95 (t,J=7.5 Hz, 2H), 2.87 (s, 3H), 1.88-1.77 (m, 2H). LCMS (ES+) m/z 422.0(M+1).

Example 3535-amino-2-(2,6-difluorophenyl)-N-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide353 Step 1: 1-(2-Fluoroethyl)-4-nitro-1H-pyrazole

1-Bromo-2-fluoroethane (5 g, 38.5 mmol) was added to a stirred mixtureof 4-nitro-1H-pyrazole (4.35 g, 38.5 mmol) and K₂CO₃ (13.3 g, 96.3 mmol)in MeCN (120 mL). The mixture was stirred at room temperature for 30 minand then heated to 50° C. for 18 hr. The mixture was cooled and thesolid filtered and washed with MeCN. The filtrate was concentrated underreduced pressure and the crude residue purified via silica gelchromatography (0-100% EtOAc/isohexane) to give1-(2-fluoroethyl)-4-nitro-1H-pyrazole as a colourless solid (5.13 g,84%). ¹H NMR (400 MHz, CDCl₃) δ 8.24 (s, 1H), 8.11 (s, 1H), 4.89-4.72(m, 2H), 4.57-4.40 (m, 2H)

Step 2: Following the procedure for Example 230 starting with1-(2-fluoroethyl)-4-nitro-1H-pyrazole gave 353 as a cream solid (137 mg,50% yield over three steps). ¹H NMR (400 MHz, d₄-MeOD) δ 8.07 (s, 1H),7.73 (d, J=0.7 Hz, 1H), 7.53-7.42 (m, 1H), 7.18-7.09 (m, 2H), 4.75 (dt,J=47.2, 4.8 Hz, 2H), 4.43 (dt, J=26.7, 4.8 Hz, 2H). LCMS (ES+) m/z 368(M+1)

Example 3545-Amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluoro-3-methoxyphenyl)thiazole-4-carboxamide354

A solution of PyBOP (211 mg, 0.406 mmol) and5-(tert-butoxycarbonylamino)-2-(2,6-difluoro-3-methoxyphenyl)thiazole-4-carboxylicacid (118 mg, 0.31 mmol) in DCM (3 mL) was stirred at room temperaturefor 30 min. A solution of tert-butyl(1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methylcarbamate (89mg, 0.29 mmol) and DIPEA (81 μL, 0.46 mmol) in DCM (3 mL) was added andthe mixture stirred at room temperature for 16 hr. The mixture wasdiluted with DCM and washed with water. The organic layer was separated,passed through a phase separation cartridge and concentrated underreduced pressure. The residue was purified via silica gel columnchromatography (0-100% EtOAc/isohexane). The isolated intermediate wasre-dissolved in DCM (10 mL) and TFA (2 mL) added. The mixture wasstirred at room temperature for 3 hr. The mixture was concentrated underreduced pressure and the residue purified by preparative HPLC to yield354 as a white solid (31 mg, 42%). ¹H NMR (400 MHz, d₄-MeOD) δ 7.58 (s,1H), 7.37-6.99 (m, 1H), 7.06 (t, J=10.0 Hz, 1H), 3.93 (s, 3H), 3.73 (s,3H), 3.29-3.04 (m, 4H), 2.65 (d, J=6.5 Hz, 2H), 1.85 (d, J=12.4 Hz, 2H),1.70-1.42 (m, 1H), 1.48-1.21 (m, 2H). LCMS (ES+) m/z 478 (M+1).

Example 355(R)-5-Amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-cyanophenyl)thiazole-4-carboxamide355

A mixture of (R)-tert-butyl2-bromo-4-(1-methyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate(122 mg, 0.20 mmol), potassium fluoride dihydrate (62 mg, 0.66 mmol) and2-cyanophenylboronic acid (88 mg, 0.60 mmol) in THF (3 mL) was degassedby gently bubbling nitrogen through the mixture for 15 min.Tris(dibenzylideneacetone)dipalladium/tri-tert-butyl phosphoniumtetrafluoroborate mixture (mole ratio: 1/1.2) (24 mg, 0.020 mmol) wasthen added and the mixture degassed for a further 10 min before beingheated in a microwave at 80° C. for 2 hr. Water was added and themixture extracted with EtOAc. The combined organic layers were passedthrough a phase separation cartridge and concentrated under reducedpressure. The residue was purified via silica gel column chromatography(0-100% EtOAc/isohexane). The isolated intermediate was dissolved in amixture of DCM (1.5 mL) and TFA (0.5 mL) and stirred at room temperaturefor 4 hr. The solvents were removed under reduced pressure and theresidue dissolved in MeOH/water (3 mL, 3:1) and K₂CO₃ (66 mg, 0.48 mmol)added. The mixture was heated at 80° C. for 6 hr. The solvents wereremoved under reduced pressure and the residue purified by preparativeHPLC to yield 355 as an orange solid (36 mg, 51%). ¹H NMR (400 MHz,d₄-MeOD) δ 7.87 (d, J=7.8 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.74 (t,J=7.8 Hz, 1H), 7.68 (s, 1H), 7.55 (t, J=7.8 Hz, 1H), 3.75 (s, 3H),3.40-3.26 (m, 4H), 3.18-3.10 (m, 1H), 2.05-1.86 (m, 3H), 1.87-1.67 (m,3H). LCMS (ES+) m/z 437 (M+1).

Example 3565-amino-N-(1-methyl-1H-pyrazol-4-yl)-2-(3-(morpholinomethyl)phenyl)thiazole-4-carboxamide356 Step 1: tert-Butyl2-bromo-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

Coupling of 1-methyl-1H-pyrazol-4-amine and2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxylic acid gavetert-butyl2-bromo-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (0.32g, 74%). ¹H NMR (400 MHz, CDCl₃) δ 10.31 (s, 1H), 8.62 (s, 1H), 7.91 (s,1H), 7.54 (s, 1H), 3.90 (s, 3H), 1.53 (s, 9H)

Step 2: Following Example 278, Suzuki coupling of tert-butyl2-bromo-4-(1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate and3-(4-morpholinomethyl)phenylboronic acid pinacol ester gave 356 as anoff-white solid (31 mg, 36% over two steps). ¹H NMR (400 MHz, d₆-DMSO) δ9.80 (s, 1H), 7.98 (s, 1H), 7.80-7.73 (m, 2H), 7.65 (s, 1H), 7.49-7.38(m, 3H), 7.35 (d, J=7.6 Hz, 1H), 3.82 (s, 3H), 3.60 (t, J=4.5 Hz, 4H),3.53 (s, 2H), 2.45-2.33 (m, 4H). LCMS (ES+) m/z 399 (M+1)

Example 357(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-fluoro-2-hydroxyphenyl)thiazole-4-carboxamide357 Following Example 278, Suzuki coupling of (R)-benzyl1-(4-(5-amino-2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamateand 5-fluoro-2-hydroxyphenylboronic acid gave 357 as a yellow solid (12mg, 21% over two steps). ¹H NMR (400 MHz, d₆-DMSO with D₂O) δ 7.80 (dd,J=10.1, 3.3 Hz, 1H), 7.42 (s, 1H), 6.94 (td, J=8.5, 3.4 Hz, 1H), 6.77(dd, J=9.0, 4.9 Hz, 1H), 3.63 (s, 3H), 3.23-3.04 (m, 6H), 1.93-1.76 (m,3H), 1.68-1.51 (m, 3H). LCMS (ES+) m/z 446 (M+1) Example 358(R)-5-Amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-cyano-2-fluorophenyl)thiazole-4-carboxamide358

Following the procedure for Example 323 starting with (R)-benzyl1-(4-(5-tert-butoxycarbonyl-amino-2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamateand 5-cyano-2-fluorophenylboronic acid gave 358 as a yellow solid (30mg, 89%). ¹H NMR (400 MHz, d₆-DMSO) δ 9.13 (s, 1H), 8.81 (dd, J=7.0, 2.2Hz, 1H), 7.95-7.90 (m, 1H), 7.62 (dd, J=11.3, 8.6 Hz, 1H), 7.53 (s, 2H),7.40 (s, 1H), 3.66 (s, 3H), 3.21-3.08 (m, 4H), 3.14-2.86 (m, 1H),1.86-1.77 (m, 3H), 1.59-1.50 (m, 3H). LCMS (ES+) m/z 455 (M+1).

Example 359(S)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-5-fluoro-6-(2-fluorophenyl)picolinamide359

Following procedures from Examples 141, (S)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate was convertedto 359. ¹H NMR (400 MHz, DMSO) δ 8.23 (dd, J=8.6, 3.8 Hz, 1H), 8.09 (t,J=9.1 Hz, 1H), 7.81 (t, J=7.4 Hz, 1H), 7.67-7.55 (m, 2H), 7.50-7.34 (m,2H), 3.65 (s, 3H), 3.18-2.99 (m, 5H), 2.91 (t, J=8.7 Hz, 1H), 1.85-1.62(m, 3H), 1.61-1.34 (m, 3H). MS (ESI) m/z: 427.2 [M+H⁺].

Example 3605-amino-N-(5-((trans-4-aminocyclohexylamino)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide360

Following the procedures provided in Example 340, 360 was obtained. ¹HNMR (400 MHz, DMSO) δ 8.83 (s, 1H), 7.64-7.38 (m, 4H), 7.26 (t, J=8.6Hz, 2H), 4.53 (d, J=7.5 Hz, 1H), 3.60 (s, 3H), 2.72 (m, 1H), 1.80 (d,J=11.8 Hz, 2H), 1.71 (d, J=11.9 Hz, 2H), 1.19 (dd, J=23.9, 10.8 Hz, 2H),0.98 (q, J=10.7 Hz, 2H). MS (ESI) m/z: 448.2 [M+H⁺].

Example 3615-amino-2-(2,6-difluorophenyl)-N-(5-(4-hydroxycyclohexyl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide361

5-Amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(4-oxocyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide(57 mg, 0.13 mmol), prepared according to the procedures provided inExample 347, was dissolved in methanol (2 mL). Sodium borohydride (15.1mg, 0.40 mmol) was added. The mixture was stirred at RT for 1 h,quenched with sat. NaHCO3 and extracted with ethyl acetate three times.Combined organic layers were concentrated and purified via reverse phaseHPLC to give 361. ¹H NMR (400 MHz, DMSO) δ 8.69 (s, 1H), 7.61-7.48 (m,2H), 7.46 (s, 2H), 7.26 (dd, J=14.5, 5.8 Hz, 2H), 4.57 (d, J=4.4 Hz,1H), 3.76 (s, 3H), 3.50-3.34 (m, 1H), 3.02 (td, J=6.6, 4.0 Hz, 1H),2.84-2.60 (m, 1H), 1.91 (d, J=9.9 Hz, 2H), 1.84-1.59 (m, 5H), 1.37-1.17(m, 2H). MS (ESI) m/z: 434.2 [M+H⁺].

Example 3625-amino-N-(5-((trans-3-aminocyclohexylamino)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide362

Following the procedures provided in Examples 340 and 346, racemic 362was obtained. The trans diastereoisomers were isolated via chiralpreparative HPLC. ¹H NMR (400 MHz, DMSO) δ 8.88 (s, 1H), 7.63-7.38 (m,4H), 7.26 (t, J=8.6 Hz, 2H), 4.50 (d, J=8.0 Hz, 1H), 3.61 (s, 3H), 3.05(d, J=3.1 Hz, 1H), 1.68-1.03 (m, 10H). MS (ESI) m/z: 448.2 [M+H⁺].

Example 3635-amino-N-(1-benzyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide363

Following the procedure for Example 304 starting with1-benzyl-1H-pyrazol-4-amine gave 363 as a pale orange gum (114 mg, 37%over two steps) ¹H NMR (400 MHz, d₄-MeOD) δ 8.06 (d, J=0.7 Hz, 1H), 7.71(d, J=0.7 Hz, 1H), 7.52-7.42 (m, 1H), 7.40-7.26 (m, 5H), 7.17-7.08 (m,2H), 5.32 (s, 2H). LCMS (ES+) m/z 412 (M+1)

Example 364(R)-5-Amino-N-(5-(4-aminoazepan-1-yl)-1-ethyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide364

Following the procedure for Example 241 starting with (R)-tert-butyl2-(2-fluorophenyl)-4-(1-ethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamategave, after preparative HPLC, 364 as a brown solid (25 mg, 9%). ¹H NMR(400 MHz, d₆-DMSO) δ 8.91 (s, 1H), 8.30-8.23 (m, 1H), 7.59 (s, 1H),7.50-7.42 (m, 3H), 7.42-7.30 (m, 2H), 4.05-3.92 (m, 2H), 3.22-2.99 (m,7H), 1.93-1.77 (m, 3H), 1.64-1.47 (m, 3H), 1.34 (t, J=7 Hz, 3H). LCMS(ES+) m/z 444.0 (M+1).

Example 365(R)-5-Amino-N-(5-(4-aminoazepan-1-yl)-1-cyclopropyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide365

Following the procedure for Example 241 starting with (R)-tert-butyl2-(2-fluorophenyl)-4-(1-cyclopropyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamategave, after preparative HPLC, 365 as a brown solid (147 mg, 58%). ¹H-NMR(400 MHz, d₆-DMSO) δ 8.90 (s, 1H), 8.30-8.20 (m, 1H), 7.53 (s, 1H),7.49-7.41 (m, 3H), 7.40-7.33 (m, 2H), 3.60-3.50 (m, 1H), 3.28-3.13 (m,4H), 3.06 (s, 1H), 1.93-1.83 (m, 3H), 1.70-1.50 (m, 5H), 1.10-1.00 (m,2H), 1.00-0.91 (m, 2H). LCMS (ES+) m/z 456.0 (M+1).

Example 366(R)-5-Amino-N-(5-(4-aminoazepan-1-yl)-1-cyclopropylmethyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide366

Following the procedure for Example 241 starting with (R)-tert-butyl2-(2-fluorophenyl)-4-(1-cyclopropylmethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamategave, after preparative HPLC, 366 as the monoformate salt as a brownsolid (109 mg, 40%). ¹H-NMR (400 MHz, d₆-DMSO) δ 8.95 (s, 1H), 8.44 (s,1H), 8.32-8.27 (m, 1H), 8.29 (m, 1H), 7.50-7.32 (m, 5H), 3.89-3.78 (m,2H), 3.24-3.06 (m, 7H), 2.06-1.89 (m, 3H), 1.89-1.80 (m, 1H), 1.77-1.57(m, 2H), 1.31-1.19 (m, 1H), 0.56-0.48 (m, 2H), 0.43-0.33 (m, 2H). LCMS(ES+) m/z 470.0 (M+1)

Example 3675-amino-N-(1-(3-aminopropyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide367 Step 1: tert-Butyl3-(7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazol-1-yl)propylcarbamate

Sodium hydride (60% dispersion in mineral oil, 0.3 g, 7.5 mmol) wasadded portion-wise to a stirred solution of2,3-dihydro-1H-pyrazolo[1,5-a]imidazole (0.68 g, 6.19 mmol) in anhydrousDMF (5 mL) at room temperature under a nitrogen atmosphere. The mixturewas cooled to 0° C. and stirred for 15 min before a solution oftert-butyl 3-bromopropylcarbamate (1.47 g, 6.19 mmol) in DMF (5 mL) wasadded portionwise over 5 min. The reaction was warmed to roomtemperature and stirred for 66 hr at room temperature. Water (5 mL) wasadded dropwise and the mixture was concentrated under reduced pressure.More water was added and the mixture was extracted with EtOAc. Thecombined organics were dried over MgSO₄ and concentrated under reducedpressure. The crude residue was purified via silica gel chromatography(0-100% EtOAc/isohexane) to give tert-butyl3-(2,3-dihydro-1H-pyrazolo[1,5-a]imidazol-1-yl)propylcarbamate as anorange oil (0.51 g, 31%). To a solution of this oil in conc. H₂SO₄ at 0°C. was added conc. HNO₃ portionwise over 5 min. The reaction was warmedto room temperature and the mixture was stirred for 18 h. The mixturewas re-cooled to 0° C., poured into ice water with stirring and basifiedwith 40% aq. NaOH. The product was extracted into DCM and the combinedorganics were dried over MgSO₄ and concentrated under reduced pressureto afford3-(7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazol-1-yl)propan-1-amine asa brown gum. This gum was dissolved in DCM (30 mL) and DIPEA (1 mL) anddi-tert-butyl dicarbonate (0.5 g, 2.3 mmol) were added. The mixture wasstirred at room temperature for 2 hr. The solvents were removed underreduced pressure and the residue was purified via silica gelchromatography (0-100% EtOAc/isohexane) to give tert-butyl3-(7-nitro-2,3-dihydro-1H-pyrazolo[1,5-a]imidazol-1-yl)propylcarbamateas a pale yellow gum (100 mg, 17% over two steps). ¹H NMR (400 MHz,CDCl₃) δ 7.82 (s, 1H), 4.82 (s br, 1H), 4.26-4.16 (m, 2H), 4.12-4.00 (m,2H), 3.84-3.72 (m, 2H), 3.23 (q, J=6.6 Hz, 2H), 1.89-1.78 (m, 2H), 1.44(s, 9H)

Step 2: Following the procedure for Example 243 starting with tert-butyl3-(7-nitro-2,3-dihydro-1H-pyrazolo[1,5-c]imidazol-1-yl)propylcarbamategave 367 as the mono-formate salt as an off-white foam (58 mg, 46% overthree steps). ¹H NMR (400 MHz, d₆-DMSO) δ 8.44 (s, 1H), 7.59-7.50 (m,3H), 7.31-7.22 (m, 2H), 7.21 (s, 1H), 4.08 (t, J=7.8 Hz, 2H), 3.71 (t,J=7.8 Hz, 2H), 3.08 (t, J=6.4 Hz, 2H), 2.84 (t, J=6.4 Hz, 2H), 1.77-1.68(m, 2H). LCMS (ES+) m/z 420 (M+1)

Example 368(S)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)pyrimidine-4-carboxamide368

Following the procedures from Example 330, (S)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate was convertedto 368. ¹H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 8.38 (br, 1H), 8.12 (dd,J=8.2, 6.5 Hz, 1H), 7.66 (s, 1H), 7.52-7.45 (m, 1H), 7.36-7.30 (m, 2H),7.07 (br, 2H), 3.69 (s, 3H), 3.19 (dd, J=8.8, 3.6 Hz, 10H), 2.04-1.76(m, 3H), 1.67 (t, J=8.5 Hz, 3H). MS (ESI) m/z: 425.2 [M+H⁺].

Example 3695-amino-N-(5-(4-aminocyclohexyl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide369 Step 1: tert-butyl2-(2,6-difluorophenyl)-4-(1-methyl-5-(4-oxocyclohexyl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

In a 50 mL round bottom flask,5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(4-oxocyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide(235 mg, 0.54 mmol, prepared according to the procedures provided inExample 347 was dissolved in anhydrous THF (10 mL).Di-tert-butyl-di-carbonate (143 mg, 0.65 mmol) and DMAP (68 mg, 0.54mmol) were added and the mixture was stirred at room temperature for 45min. The reaction was concentrated and purified via flash chromatography(0 to 100% ethyl acetate in heptane) to give tert-butyl2-(2,6-difluorophenyl)-4-(1-methyl-5-(4-oxocyclohexyl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate(68 mg, 23%)

Step 2: tert-butyl2-(2,6-difluorophenyl)-4-(5-(4-hydroxycyclohexyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate

tert-Butyl2-(2,6-difluorophenyl)-4-(1-methyl-5-(4-oxocyclohexyl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate(68 mg, 0.13 mmol) was dissolved in methanol (3 mL) and sodiumborohydride (16 mg, 0.39 mmol) was added. The mixture was stirred at RTfor 30 min then quenched with sat. NaHCO3 and extracted with ethylacetate three times. Combined organic layers were dried over sodiumsulfate, filtered and concentrated to give the crude tert-butyl2-(2,6-difluorophenyl)-4-(5-(4-hydroxycyclohexyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate(58 mg, 85%).

Step 3: tert-butyl4-(5-(4-azidocyclohexyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate

tert-Butyl2-(2,6-difluorophenyl)-4-(5-(4-hydroxycyclohexyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate(58 mg, 0.11 mmol) was dissolved in methylene chloride (3 mL) and THF(1.5 mL). Triethylamine (33 mg, 0.33 mmol) and methanesulfonyl chloride(19 mg, 0.16 mmol) were added and the mixture was stirred at roomtemperature for 2.5 h. The reaction was diluted with ethyl acetate (50mL), washed with sat. sodium bicarbonate and brine and concentrated invacuo (65 mg). The residue was dissolved in NMP (3.0 mL) and sodiumazide (21.4 mg, 0.33 mmol) was added. The mixture was stirred at 85° C.overnight. After cooling to room temperature, the reaction was dilutedwith ethyl acetae, washed with water and brine, dried over sodiumsulfate and concentrated in vacuo. The residue was purified via flashchromatography, eluted with 0 to 100% ethyl acetate in heptane to givetert-butyl4-(5-(4-azidocyclohexyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate(18 mg, 30%).

Step 4: tert-butyl4-(5-(4-aminocyclohexyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate

tert-Butyl4-(5-(4-azidocyclohexyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate(18 mg, 0.032 mmol) was dissolved in THF (2 mL) and water (0.5 mL).Triphenylphosphine (21.5 mg, 0.083 mmol) was added and the mixture washeated at 60° C. overnight. After cooling to room temperature, thereaction was quenched with water and extracted with methylene chloridethree times to give the crude product tert-butyl4-(5-(4-aminocyclohexyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate.

Step 5: tert-Butyl4-(5-(4-aminocyclohexyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamatewas stirred with 4.0M HCl in dioxane (5 mL) for 2 h. Solvent was removedin vacuo, and the residue was basified with sat. sodium bicarbonate andextracted with ethyl acetate 3×. Combined organic layers wereconcentrated and purified via reverse phase HPLC to give 369. ¹H NMR(400 MHz, DMSO) δ 8.82 (s, 1H), 8.35 (s, 1H), 7.60-7.36 (m, 3H), 7.27(t, J=8.7 Hz, 1H), 3.80 (s, 3H), 2.77 (t, J=12.3 Hz, 1H), 2.13-1.94 (m,2H), 1.67 (dt, J=29.6, 13.3 Hz, 5H). MS (ESI) m/z: 433.2 [M+H⁺].

Example 370(S)-5-amino-N-(5-(azepan-4-ylamino)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide370 Step 1: (S)-tert-Butyl4-(1-methyl-4-nitro-1H-pyrazol-5-ylamino)azepane-1-carboxylate

Following the procedure for Example 332 starting with (S)-tert-butyl4-(benzyloxycarbonylamino)azepane-1-carboxylate and5-chloro-1-methyl-4-nitro-1H-pyrazole gave (S)-tert-butyl4-(1-methyl-4-nitro-1H-pyrazol-5-ylamino)azepane-1-carboxylate as ayellow viscous oil (103 mg, 49%). ¹H NMR (400 MHz, CDCl₃) δ 7.90 (s,1H), 6.60-6.50 (m, 1H), 3.80 (s, 3H), 3.79-3.67 (m 1H), 3.60-3.52 (m,1H), 3.49-3.44 (m, 1H), 3.44-3.22 (m, 2H), 2.25-2.10 (m, 1H), 2.05-1.62(m, 5H), 1.48 (s, 9H)

Step 2: Following the procedure for Example 243 starting with(S)-tert-butyl4-(1-methyl-4-nitro-1H-pyrazol-5-ylamino)azepane-1-carboxylate gave 370as a cream solid (35 mg, 27% over three steps). ¹H NMR (400 MHz, CDCl₃)δ 8.46 (s, 1H), 8.41 (s br, 1H), 7.46 (s, 1H), 7.34-7.30 (m, 1H),7.06-6.98 (m, 3H), 6.21 (s br, 1H), 3.73 (s, 3H), 3.28-3.20 (m, 2H),3.15-3.00 (m, 2H), 3.00-2.90 (m, 1H), 2.15-2.08 (m, 1H), 2.05-1.85 (m,3H), 1.70-1.60 (m, 2H). Alkyl NH not seen. LCMS (ES+) m/z 448 (M+1)

Example 3715-amino-N-(5-(2-(aminomethyl)morpholino)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide371 Step 1: tert-Butyl(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)morpholin-2-yl)methylcarbamate

Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and tert-butylmorpholin-2-ylmethylcarbamate gave tert-butyl(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)morpholin-2-yl)methylcarbamate as ayellow oil (196 mg, 93%). ¹H NMR (400 MHz, CDCl₃) δ 8.04 (s, 1H), 4.92(s br, 1H), 4.00 (dd, J=11.3, 2.9 Hz, 1H), 3.90-3.68 (m, 5H), 3.57 (td,J=11.6, 3.2 Hz, 1H), 3.38-3.24 (m, 2H), 3.15 (ddd, J=14.1, 7.1, 5.1 Hz,1H), 2.86 (d, J=11.8 Hz, 1H), 2.77 (d, J=11.8 Hz, 1H), 1.45 (s, 9H)

Step 2: tert-Butyl(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)morpholin-2-yl)methylcarbamate wasdeprotected under acidic conditions. Following the procedure for Example243 starting with(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)morpholin-2-yl)methanamine gave 371as a cream solid (102 mg, 41% over three steps). ¹H NMR (400 MHz, CDCl₃)δ 8.47 (s, 1H), 7.74 (s, 1H), 7.39-7.24 (m, 1H), 7.07-6.99 (m, 2H), 6.15(s, 2H), 3.99 (dd, J=11.3, 2.8 Hz, 1H), 3.87-3.73 (m, 4H), 3.62 (ddt,J=9.5, 7.3, 3.2 Hz, 1H), 3.33 (td, J=11.3, 3.2 Hz, 1H), 3.12-2.87 (m,3H), 2.85-2.70 (m, 2H). LCMS (ES+) m/z 450 (M+1)

Example 372(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-chloro-2-fluorophenyl)thiazole-4-carboxamide372

Following the procedures from Examples 140, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16was converted to Boc and Cbz protected intermediate. This intermediatewas heated with 3N aqueous HCl (12 mL) for 4 h and concentrated underreduced pressure. The residue was basified with sat. sodium bicarbonate,extracted with ethyl acetate, and purified via reverse phase PHLC togive 372. ¹H NMR (400 MHz, DMSO) δ 9.04 (s, 1H), 8.33 (dd, J=6.5, 2.6Hz, 1H), 7.53-7.35 (m, 5H), 3.65 (s, 3H), 3.22-2.91 (m, 6H), 1.83 (d,J=10.6 Hz, 4H), 1.69-1.40 (m, 5H). MS (ESI) m/z: 464.2 [M+H⁺].

Example 373(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-bromo-2-fluorophenyl)thiazole-4-carboxamide373

Following the procedures from Example 372, 373 was obtained. ¹H NMR (400MHz, DMSO) δ 8.92 (s, 1H), 8.25 (t, J=6.9 Hz, 1H), 7.73 (t, J=6.7 Hz,1H), 7.49 (s, 3H), 7.30 (t, J=8.0 Hz, 1H), 6.59 (s, 1H), 3.65 (s, 3H),3.13 (dd, J=34.5, 22.1 Hz, 6H), 1.94-1.74 (m, 3H), 1.70-1.39 (m, 3H). MS(ESI) m/z: 508.1/510.1 [M+H⁺].

Example 374(S)-5-amino-2-(2,6-difluorophenyl)-N-(5-(4-hydroxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide374 and Example 375(R)-5-amino-2-(2,6-difluorophenyl)-N-(5-(4-hydroxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide375

The racemic compound 189 from Example 189 was resolved on chiralpreparative HPLC to separate the (5) enantiomer 374 and the (R)enantiomer 375. ¹H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 7.58-7.39 (m,4H), 7.26 (t, J=8.7 Hz, 2H), 4.43 (d, J=3.7 Hz, 1H), 3.91-3.74 (m, 1H),3.64 (s, 3H), 3.24-3.09 (m, 2H), 3.09-2.93 (m, 2H), 2.07 (s, 1H), 1.87(dd, J=18.2, 10.9 Hz, 3H), 1.75-1.46 (m, 3H). MS (ESI) m/z: 449.2[M+H⁺].

Example 3765-amino-N-(5-(4-hydroxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(pyridin-2-yl)thiazole-4-carboxamide376

Following the procedures from Example 140,1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ol, prepared according tothe procedures from Example 189, and5-(tert-butoxycarbonylamino)-2-(yridine-2-yl)thiazole-4-carboxylic acidfrom Example 31 were converted to 376. ¹H NMR (400 MHz, DMSO) δ 8.79 (s,1H), 8.54 (d, J=4.7 Hz, 1H), 8.14 (d, J=7.9 Hz, 1H), 7.89 (t, J=7.6 Hz,1H), 7.54 (m, 3H), 7.43-7.34 (m, 1H), 4.58 (d, J=3.6 Hz, 1H), 3.90-3.82(m, 1H), 3.66 (s, 3H), 3.24-2.99 (m, 4H), 2.00-1.55 (m, 6H). MS (ESI)m/z: 414.2 [M+H⁺].

Example 377(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,3-difluorophenyl)thiazole-4-carboxamide377

Following the procedures from Example 140, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16and5-(tert-butoxycarbonylamino)-2-(2,3-difluorophenyl)thiazole-4-carboxylicacid from Example 42 were converted to 377. ¹H NMR (400 MHz, DMSO) δ8.92 (br, 1H), 8.06 (t, J=7.2 Hz, 1H), 7.62-7.39 (m, 4H), 7.34 (dd,J=13.1, 7.8 Hz, 1H), 3.66 (s, 4H), 3.20-3.01 (m, 5H), 1.92-1.76 (m, 3H),1.71-1.47 (m, 3H). MS (ESI) m/z: 448.2 [M+H⁺].

Example 3785-amino-N-(5-(trans-3-aminocyclohexyl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide378 Step 1: tert-butylN-[3-(2-methyl-4-nitro-pyrazol-3-yl)cyclohex-2-en-1-yl]carbamate

5-Chloro-1-methyl-4-nitropyrazole (100 mg, 0.62 mmol), tert-butylN-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-yl]carbamate(240 mg, 0.74 mmol),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (45 mg,0.061 mmol), a 1M solution of Na₂CO₃ (0.93 mL), a 1M solution ofpotassium acetate (0.93 mL) and acetonitrile (6 mL) were charged in amicrowave reaction vial, The mixture was irradiated to 140° C. with amicrowave for 30 min and cooled to room temperature. It was filteredthrough Celite and thoroughly washed with methanol. The filtrate wasconcentrated and the residue was purified via flash chromatography, 0 to100% ethyl acetate in heptane to give tert-butylN-[3-(2-methyl-4-nitro-pyrazol-3-yl)cyclohex-2-en-1-yl]carbamate (98 mg,49%)

Step 2: tert-butylN-[3-(4-amino-2-methyl-pyrazol-3-yl)cyclohexyl]carbamate

tert-ButylN-[3-(2-methyl-4-nitro-pyrazol-3-yl)cyclohex-2-en-1-yl]carbamate wasdissolved in methanol (100 mL) and hydrogenated on H-Cube at 60° C. and60 bar hydrogen pressure to give tert-butylN-[3-(4-amino-2-methyl-pyrazol-3-yl)cyclohexyl]carbamate.

Step 3:tert-butyl-3-(4-(5-Boc-amino-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)cyclohexylcarbamate

Following the procedures from Example 140, tert-butylN-[3-(4-amino-2-methyl-pyrazol-3-yl)cyclohexyl]carbamate and5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid from Example 25 were converted totert-butyl-3-(4-(5-Boc-amino-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)cyclohexylcarbamate.Trans and cis diastereoisomers were separated by flash chromatographyeluted with 0 to 100% ethyl acetate in heptane. The Rf value for transand cis isomers were 0.64 and 0.53, respectively.

Step 4: The above trans isomer was stirred with 4.0M HCl in dioxane (4mL) for 3 h. The reaction was concentrated and the residue was basifiedwith saturated sodium bicarbonate and extracted with ethyl acetate 3×.The combined organic layers were dried over sodium sulfate, filtered andconcentrated. The crude product was further purified on reverse phaseHPLC to give 378. ¹H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 7.60-7.39 (m,1H), 7.27 (t, J=8.7 Hz, 2H), 3.78 (s, 3H), 3.50-3.45 m, 1H), 3.30-3.20(m, 1H), 2.04-1.44 (m, 8H). MS (ESI) m/z: 433.2 [M+H⁺]

Example 3795-amino-N-(5-(cis-3-aminocyclohexyl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide379

The cis isomer from the preparation of Example 378 was stirred with 4.0MHCl in dioxane (4 mL) for 3 h. The reaction was concentrated and theresidue was basified with saturated sodium bicarbonate and extractedwith ethyl acetate 3×. The combined organic layers were dried oversodium sulfate, filtered and concentrated. The crude product was furtherpurified on reverse phase HPLC to give 379. ¹H NMR (400 MHz, DMSO) δ8.70 (s, 1H), 7.62-7.37 (m, 4H), 7.26 (t, J=8.8 Hz, 2H), 3.77 (s, 3H),2.84 (t, J=12.4 Hz, 1H), 2.74-2.60 (m, 1H), 1.85-1.70 (m, 4H), 1.62-1.50(m, 1H), 1.45-1.35 (m, 2H), 1.08-0.98 (m, 1H). MS (ESI) m/z: 433.2[M+H⁺]

Example 380(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(pyridin-2-yl)thiazole-4-carboxamide380

Following the procedures from Example 140, (R)-benzyl1-(4-amino-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate from Example 16and5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid from Example 25 were converted to 380. ¹H NMR (400 MHz, DMSO) δ8.85 (s, 1H), 8.54 (d, J=4.7 Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.91 (td,J=7.8, 1.5 Hz, 1H), 7.62-7.43 (m, 3H), 7.38 (dd, J=6.9, 5.2 Hz, 1H),3.65 (s, 3H), 3.22-2.98 (m, 5H), 1.99-1.74 (m, 3H), 1.72-1.49 (m, 3H).MS (ESI) m/z: 413.2 [M+H⁺]

Example 381(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-3-methylphenyl)thiazole-4-carboxamide381

Boc and Cbz protected intermediate of 373 from Example 373, wassubjected to standard Suzuki conditions, following procedures in Example141 with methyl boronic acid to give the methylated intermediate.Deprotection according to procedures for Example 373, gave 381. ¹H NMR(400 MHz, DMSO) δ 8.89 (s, 1H), 8.07 (t, J=7.2 Hz, 1H), 7.52 (s, 1H),7.40 (s, 2H), 7.32 (t, J=6.9 Hz, 1H), 7.22 (t, J=7.7 Hz, 1H), 6.74 (s,1H), 3.65 (s, 4H), 3.23-2.95 (m, 8H), 2.31 (s, 3H), 1.95-1.72 (m, 4H),1.72-1.44 (m, 4H). MS (ESI) m/z: 444.2 [M+H⁺].

Example 382(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-cyclopropyl-2-fluorophenyl)thiazole-4-carboxamide382 Step 1: tricyclopropylbismuthane

Trichlorobismuthane (1.25 g; 3.96 mmol) was dissolved in anhydrous THF(50 mL) and cooled to −10° C. Cyclopropylmagnesium bromide (0.5M in THF,15 mmol; 30 mL) was added via dropping funnel over 30 min, keeping thetemperature at −10° C. The reaction mixture was stirred at RT for 1 hthen heated at 70° C. for 30 min, at which time a black precipitate wasobserved. After cooling to RT, the solution was cannulated undernitrogen over a degassed biphasic solution of brine (100 ml) and ether(100 ml). The heterogeneous solution was stirred for 5 min, transferredto a separatory funnel and diluted with ether (50 ml). The organic phasewas collected, dried over sodium sulfate, filtered and concentratedunder reduced pressure to give a yellow oily solid. Ether (25 ml) wasadded followed by hexane (25 ml). The mixture was sonicated, cooled to0° C., and filtered to collect the light yellow solid,tricyclopropylbismuthane (770 mg, 58%).

Step 2: (R)-tert-butyl4-(5-(4-Cbz-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(3-cyclopropyl-2-fluorophenyl)thiazol-5-ylcarbamate

In a 40 mL reaction vial, the Boc and Cbz protected intermediate ofcompound 373, tert-butylN-[4-[[5-[(4R)-4-(benzyloxycarbonylamino)azepan-1-yl]-1-methyl-pyrazol-4-yl]carbamoyl]-2-(3-bromo-2-fluoro-phenyl)thiazol-5-yl]carbamate(200 mg; 0.2693 mmol):

tricyclopropylbismuthane (134 mg, 0.4039 mmol), palladium(0)tetrakis(triphenylphosphine) (31 mg, 0.027 mmol), potassium carbonate(75 mg, 0.54 mmol) and DMF (3 mL) were mixed. The reaction vial wasvacuum purged and filled with notrogen. The vial was sealed and heatedat 90° C. overnight. The mixture was cooled to RT, diluted with sat.sodium bicarbonate and extracted with ethyl acetate (2×). The combinedorganic layers were back washed with sat. sodium bicarbonate and brine,dried over sodium sulfate, filtered and concentrated. The crude productwas purified via flash chromatography, eluted with 0 to 7% methanol inDCM to give (R)-tert-butyl4-(5-(4-Cbz-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(3-cyclopropyl-2-fluorophenyl)thiazol-5-ylcarbamate(104 mg, 55%).

Step 3: (R)-tert-butyl4-(5-(4-Cbz-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(3-cyclopropyl-2-fluorophenyl)thiazol-5-ylcarbamatewas heated with 3N aqueous HCl (6 mL) overnight. Only Boc deprotectionwas observed. The reaction was concentrated under reduced pressure andthe residue was re-dissolved in methanol (100 mL).

The methanol solution was hydrogenated on H-Cube at 40° C. and 30 barhydrogen pressure. The solution was concentrated and purified viareverse phase PHLC to give 382. ¹H NMR (400 MHz, DMSO) δ 8.89 (br, 1H),8.03 (t, J=6.9 Hz, 1H), 7.52 (s, 1H), 7.40 (br, 2H), 7.21 (t, J=7.8 Hz,1H), 7.02 (t, J=6.9 Hz, 1H), 3.65 (s, 3H), 3.22-2.95 (m, 5H), 2.12 (ddd,J=13.7, 8.5, 5.2 Hz, 2H), 1.84 (t, J=9.5 Hz, 3H), 1.70-1.42 (m, 3H),1.05-0.93 (m, 2H), 0.82-0.68 (m, 2H). MS (ESI) m/z: 470.2 [M+H⁺].

Example 383(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-ethyl-2-fluorophenyl)thiazole-4-carboxamide383 Step 1: tert-butylN-[4-[[5-[(4R)-4-(benzyloxycarbonylamino)azepan-1-yl]-1-methyl-pyrazol-4-yl]carbamoyl]-2-(2-fluoro-3-vinyl-phenyl)thiazol-5-yl]carbamate

The Boc and Cbz protected intermediate of compound 373 from Example 373,tert-butylN-[4-[[5-[(4R)-4-(benzyloxycarbonylamino)azepan-1-yl]-1-methyl-pyrazol-4-yl]carbamoyl]-2-(3-bromo-2-fluoro-phenyl)thiazol-5-yl]carbamate,(158 mg; 0.213 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane(98 mg, 0.11 mmol),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (16 mg,0.021 mmol), a 1M solution of Na₂CO₃ (0.32 mL), a 1M solution ofpotassium acetate (0.32 mL) and acetonitrile (3.5 mL) were charged in amicrowave reaction vial. The mixture was irradiated to 130° C. with amicrowave for 30 min and cooled to room temperature. It was filteredthrough Celite and thoroughly washed with methanol. The filtrate wasconcentrated and the residue was purified via flash chromatography, 0 to100% ethyl acetate in heptane to give tert-butylN-[4-[[5-[(4R)-4-(benzyloxycarbonylamino)azepan-1-yl]-1-methyl-pyrazol-4-yl]carbamoyl]-2-(2-fluoro-3-vinyl-phenyl)thiazol-5-yl]carbamate.

Step 2: tert-butylN-[4-[[5-[(4R)-4-(benzyloxycarbonylamino)azepan-1-yl]-1-methyl-pyrazol-4-yl]carbamoyl]-2-(2-fluoro-3-vinyl-phenyl)thiazol-5-yl]carbamate(51 mg, 0.086 mmol) was dissolved in methanol (50 mL) and hydrogenatedon H-Cube at 60° C. and 50 bar hydrogen pressure to reduce the doublebond. The solution was concentrated and the residue was dissolved in DCM(5 mL). 1.0M solution of boron tribromide in methylene chloride (0.35ml, 0.35 mmol) was added and the mixture was stirred for 2 h. Thesolvent was distilled off and the residue was purified via reverse phaseHPLC to afford 383. MS (ESI) m/z: 458.3 [M+H⁺].

Example 3845-amino-N-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide384 Step 1: 1-(2,2-difluoroethyl)-4-nitro-pyrazole

4-Nitro-1H-pyrazole (150 mg, 1.33 mmol) and 1,1-difluoro-2-iodo-ethane(509 mg, 2.65 mmol) were dissolved in acetonitrile (5 mL). Cesiumcarbonate (917 mg, 2.79 mml) was added and the mixture was heated at100° C. for 40 min. After cooling down to room temperature, the reactionwas diluted with sat. ammonium chloride and extracted with methylenechloride (3×). The combined organic layers were dried over sodiumsulfate, filtered and the filtrate was concentrated to give1-(2,2-difluoroethyl)-4-nitro-pyrazole (237 mg) as a light yellow solid.

Step 2: 1-(2,2-difluoroethyl)pyrazol-4-amine

1-(2,2-difluoroethyl)-4-nitro-pyrazole (235 mg, 1.33 mmol) was dissolvedin methanol (50 mL) and hydrogenated on H-Cube at 50° C. and 40 barpressure to give 1-(2,2-difluoroethyl)pyrazol-4-amine (183 mg, 93%).

Step 3: tert-butyl4-(1-(2,2-difluoroethyl)-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate

1-(2,2-difluoroethyl)pyrazol-4-amine (183 mg, 1.24 mmol) and5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid from Example 25 were converted to tert-butyl4-(1-(2,2-difluoroethyl)-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamateaccording to the procedure provided in Example 140.

Step 4: tert-butyl4-(1-(2,2-difluoroethyl)-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamatewas stirred with 4.0M HCl in dioxane overnight. The reaction wasconcentrated and the residue was basified with sat. sodium bicarbonate.The mixture was extracted with ethyl acetate (3×), concentrated andpurified on reverse phase HPLC to afford the title compound 384. ¹H NMR(400 MHz, DMSO) δ 9.82 (s, 1H), 8.10 (s, 1H), 7.74 (s, 1H), 7.62-7.39(m, 3H), 7.26 (dd, J=14.3, 5.9 Hz, 2H), 6.32 (tt, J=54.9, 3.7 Hz, 1H),4.58 (td, J=15.1, 3.8 Hz, 2H). MS (ESI) m/z: 386.3 [M+H⁺].

Example 3855-amino-2-(2,6-difluorophenyl)-N-(1-propyl-1H-pyrazol-4-yl)thiazole-4-carboxamide385

Following the procedures provided in Example 384,1-propyl-1H-pyrazol-4-amine and5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid from Example 25 were converted to 385. ¹H NMR (400 MHz, DMSO) δ9.70 (s, 1H), 7.98 (s, 1H), 7.65 (s, 1H), 7.62-7.42 (m, 3H), 7.26 (dd,J=14.2, 5.8 Hz, 2H), 4.01 (t, J=6.9 Hz, 2H), 1.76 (dd, J=14.4, 7.2 Hz,2H), 0.83 (t, J=7.4 Hz, 3H). MS (ESI) m/z: 364.1 [M+H⁺].

Example 3865-amino-2-(2,6-difluorophenyl)-N-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide386

Following the procedures provided in Example 384,2-(4-amino-1H-pyrazol-1-yl)ethanol and5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylicacid from Example 25 were converted to 386. MS (ESI) m/z: 366.1 [M+H H⁺]

Example 387N-(5-(1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-3-amino-6-(2-fluorophenyl)picolinamide387

Following the procedures as described in Example 23 and starting withtert-butyl 1,4-diazepane-1-carboxylate, 387 was obtained as a whitesolid (22 mg, 23%) over two steps. ¹H NMR (400 MHz, DMSO) δ 9.97 (s,1H), 8.07 (dd, J=11.2, 4.9 Hz, 1H), 7.73 (dd, J=8.7, 2.2 Hz, 1H), 7.56(d, J=12.9 Hz, 2H), 7.50-7.27 (m, 4H), 7.07 (s, 2H), 6.50 (d, J=18.1 Hz,1H), 3.69 (d, J=18.7 Hz, 3H), 3.42-3.35 (m, 2H), 3.25 (t, J=5.9 Hz, 2H),3.19-3.03 (m, 4H), 1.93 (dd, J=10.8, 5.8 Hz, 2H). ESIMS m/z=410.1 (M+1).

Example 3883-amino-6-(2-fluorophenyl)-N-(1-methyl-5-(1H-pyrrolo[3,4-c]pyridin-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-1H-pyrazol-4-yl)picolinamide388

Following the procedures as described in Example 23 and starting withtert-butyl hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate, 388was obtained as a white solid (21 mg, 25%) over two steps. ¹H NMR (400MHz, DMSO) δ 8.63 (s, 1H), 7.56-7.42 (m, 4H), 7.26 (t, J=8.7 Hz, 2H),3.63 (s, 3H), 3.39-3.33 (m, 2H), 3.23-3.17 (m, 1H), 3.09 (dd, J=8.6, 3.9Hz, 1H), 2.90-2.68 (m, 4H), 2.30 (s, 2H), 1.59 (d, J=5.3 Hz, 2H). ESIMSm/z=436.1 (M+1).

Example 3895-Amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(4-cyanophenyl)thiazole-4-carboxamide389

Following Example 278, Suzuki coupling of tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateand 4-cyanophenyl boronic acid gave 389 as a green solid (26 mg 30% overtwo steps). ¹H NMR (400 MHz, d₆-DMSO) δ 9.01 (s, 1H), 8.01 (d, J=8.3 Hz,2H), 7.90 (d, J=8.3 Hz, 2H), 7.62 (s, 2H), 7.31 (s, 1H), 3.62 (s, 3H),3.12-2.96 (m, 4H), 2.45 (d, J=5.6 Hz, 2H), 2.20-1.80 (m, 2H), 1.74 (d,J=11.6 Hz, 2H), 1.26-1.14 (m, 3H). LCMS (ES+) m/z 437 (M+1)

Example 3905-Amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-fluoro-2-methoxyphenyl)thiazole-4-carboxamide390

Following Example 278, Suzuki coupling of tert-butyl4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamateand 5-fluoro-2-methoxyphenyl boronic acid gave 390 as a pale brown solid(24 mg, 26% over two steps). ¹H NMR (400 MHz, d₆-DMSO) δ 9.12 (s, 1H),8.19 (d, J=10.0 Hz, 1H), 7.36 (d, J=2.1 Hz, 1H), 7.28 (d, J=7.1 Hz, 1H),7.26-7.22 (m, 2H), 3.99 (s, 3H), 3.67 (s, 3H), 3.16-3.00 (m, 4H), 2.47(d, J=5.6 Hz, 2H), 1.78 (d, J=11.5 Hz, 2H), 1.30-1.17 (m, 3H). LCMS(ES+) m/z 460 (M+1)

Example 901 Pim Kinase Binding Activity

PIM-1, -2, and -3 enzymes were generated as fusion proteins expressed inbacteria and purified by IMAC column chromatography (Sun, X., Chiu, J.F., and He, Q. Y. (2005) Expert Rev. Proteomics, 2:649-657). Afluorescent-labeled Pim-specific peptide substrate, was customsynthesized by American Peptide Company (Sunnyvale, Calif.). ReactionBuffer contained 10 mM HEPES, pH 7.2, 10 mM MgCl₂, 0.01% Tween 20, 2 mMDTT. Termination Buffer contained 190 mM HEPES, pH 7.2, 0.015% Brij-35,0.2% Coating Reagent 3 (Caliper Life Sciences, Hopkinton, Mass.), 20 mMEDTA. Separation Buffer contained 100 mM HEPES, pH 7.2, 0.015% Brij-35,0.1% Coating Reagent 3, 1:200 Coating Reagent 8 (Caliper Life Sciences,Hopkinton, Mass.), 10 mM EDTA and 5% DMSO.

PIM reactions were carried out in a final volume of 10 μL per well in a384-well plate. A standard enzymatic reaction, initiated by the additionof 5 μL 2×ATP and test compound to 5 μL of 2× enzyme and FAM-peptide,contained 20 μM PIM1, 50 μM PIM2, or 55 pM PIM3, 1 μM FAM-peptide, and10 μM ATP, in Reaction Buffer. After 90 minutes of incubation at roomtemperature, the phosphorylation reaction was stopped by the addition of10 μL Termination Buffer. The product and substrate in each independentreaction were separated on a 12-sipper microfluidic chip (Caliper LifeSciences, Hopkinton, Mass.) run on a Caliper LC3000® (Caliper LifeSciences, Hopkinton, Mass.). The separation of product and substrate wasoptimized by choosing voltages and pressure using Caliper's Optimizersoftware (Hopkinton, Mass.). The separation conditions used a downstreamvoltage of −500V, an upstream voltage of −2150V, and a screeningpressure of −1.2 psi. The product and substrate fluorophore were excitedat 488 nm and detected at 530 nm. Substrate conversion was calculatedfrom the electropherogram using HTS Well Analyzer software (Caliper LifeSciences, Hopkinton, Mass.). Ki values for the test compound werecalculated.

PIM1 LC3K PIM2 LC3K PIM3 LC3K No. (KI) μM (KI) μM (KI) μM 102 0.016  0.110 0.0088  103 0.0065  0.0551 0.00489 105 0.00454  0.148 0.00577 1070.00122  0.0201  0.000575 109 0.000762 0.0411 0.00263 112 0.0002460.00249 0.00034 113  2.70E−05 0.000316   2.20E−05 114 0.000115 0.00165 0.000159 115 0.00114  0.0461 0.00108 116 0.00436  0.0262 0.00497 1190.000274 0.00213  0.000305 120 0.00197  0.0283 0.0011  121 0.0388  0.1540.0681  122 0.000281 0.0147  0.000962 123 0.137   0.587 0.215  1240.00192  0.0285 0.00379 129 0.000343 0.0102 0.00133 135 0.000506 0.0106 0.000344 140  2.40E−05 0.000167   1.00E−05 141 — 0.00352  0.000295 1420.000368 0.00313  0.000245 220 0.022   0.581 0.0342  231 0.00765  0.2010.00526 238 0.000897 0.0173 0.00248 263 0.0104  0.185+ 0.00612 3280.000096 0.00437  0.000176 353 0.0119  0.038 0.019  364 0.020   0.1240.024  369 0.000462 0.0125  0.000735

Example 902 In Vitro Cell Proliferation Potency Assays

BaF3 parental line was obtained from the DSMZ repository. BaF3 linestransfected with PIM 1 or PIM2 were generated. Mouse IL-3 was purchasedfrom R&D Systems. G418 was purchased from Clontech. Media for BaF3parental line contained RPMI, 10% FBS, 2 mM L-Glutamine, 2 ng/mL mIL-3.Media for BaF3 PIM1 & 2 lines contained RPMI, 10% FBS, 2 mM L-Glutamine,250 μg/mL. Media for MM1.S (multiple myeloma cells) line contained RPMI,10% FBS, 2 mM L-Glutamine.

BaF3, a murine interleukin-3 dependent pro-B cell line, parental cells,BaF3 PIM1 cells, BaF3 PIM2 cells, and MM1.S (multiple myeloma) cellswere seeded at 2 k/well, 5 k/well, 5 k/well, and 10 k/well respectively,in a 384-well plate, at 45 μL/well. Test compound was added at 5μL/well. BaF3 cells (parental and transfected) were incubated overnight,while MM1.S cells were incubated for 72 hours at 37° C., 5% CO₂. CellTiter Glo Reagent (Promega) was added at 50 μL/well, the plates wereincubated for 30 minutes, and their luminescence read on an HT Analyst.IC₅₀/EC₅₀ values for the test compound were calculated.

Representative compounds of the present invention were tested asdescribed above and found to exhibit a Ki/IC₅₀/EC₅₀ as shown below.

Prolif BaF3 Prolif BaF3 Prolif MM1S IL3 (IC50) PIM1 (IC50) ATP (EC50)No. μM μM μM 103 10.6 7.3 9.1 106 6.6 3.8 4.2 108 4.3 0.615 8.2 110 121.5 16.1 111 13.2 4.2 7.1 113 11.3 0.123 10 114 5.5 2.3 115 6.2 4.5117 >25 4.9 119 5.2 1.3 120 25 7.8 122 11.9 1.1 129 21.5 5.1 133 250.258 134 7.8 1.4 135 9.3 0.66 136 5.9 0.634 140 7.4 0.0147 141 1.10.219 143 1.1 0.377 145 3.8 1

We claim:
 1. A compound selected from Formula I:

and stereoisomers, geometric isomers, tautomers, or pharmaceuticallyacceptable salts thereof, wherein: R¹ is H, C₁-C₁₂ alkyl, C₂-C₁₂alkenyl, C₂-C₁₂ alkynyl, C₆-C₂₀ aryl, C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, or C₁-C₂₀ heteroaryl; R² is NR⁴R⁵, and R⁴ and R⁵ togetherform C₂-C₂₀ heterocyclyl or C₁-C₂₀ heteroaryl; X is selected from thestructures:

where the wavy line indicates the site of attachment; R³ is C₆-C₂₀ aryl,—(C₆-C₂₀ arylene)-(C₂-C₂₀ heterocyclyl), —(C₆-C₂₀ arylene)-(C₁-C₁₂alkylene)-(C₂-C₂₀ heterocyclyl), C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, or C₁-C₂₀ heteroaryl; R⁶ is H or —NH₂; R⁷ is H, F, CH₂F,CHF₂, and CF₃; and where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl,heterocyclyl, aryl, and heteroaryl are optionally substituted with oneor more groups independently selected from F, Cl, Br, I, —CH₃, —CH₂CH₃,—CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CHCH₂NH₂,—CH₂CH(CH₃)NH₂, —CH₂OH, —CH₂CH₂OH, —C(CH₃)₂OH, —CH(OH)CH(CH₃)₂,—C(CH₃)₂CH₂OH, —CH₂CH₂SO₂CH₃, —CN, —CF₃, —CO₂H, —COCH₃, —CO₂CH₃,—CO₂C(CH₃)₃, —COCH(OH)CH₃, —CONH₂, —CONHCH₃, —CON(CH₃)₂, —C(CH₃)₂CONH₂,—NO₂, —NH₂, —NHCH₃, —N(CH₃)₂, —NHCOCH₃, —N(CH₃)COCH₃, —NHS(O)₂CH₃,—N(CH₃)C(CH₃)₂CONH₂, —N(CH₃)CH₂CH₂S(O)₂CH₃, ═O, —OH, —OCH₃,—S(O)₂N(CH₃)₂, —SCH₃, —CH₂OCH₃, —S(O)₂CH₃, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl,pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-yl)ethyl), pyranyl,(piperidin-4-ylmethyl), morpholinomethyl, and morpholino.
 2. Thecompound of claim 1 wherein R¹ is C₁-C₁₂ alkyl.
 3. The compound of claim1 wherein R² is selected from the structures:

where the wavy line indicates the site of attachment.
 4. The compound ofclaim 1 wherein NR⁴R⁵ forms optionally substituted azepan-1-yl,piperidin-1-yl, or pyrrolidin-1-yl.
 5. The compound of claim 4 whereinazepan-1-yl, piperidin-1-yl, or pyrrolidin-1-yl is substituted with oneor more groups selected from F, Cl, Br, I, —CH₃, —CH₂CH₃, —CH(CH₃)₂,—CH₂CH(CH₃)₂, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CHCH₂NH₂, —CH₂CH(CH₃)NH₂, —CH₂OH,—CH₂CH₂OH, —C(CH₃)₂OH, —CH(OH)CH(CH₃)₂, —C(CH₃)₂CH₂OH, —CH₂CH₂SO₂CH₃,—CN, —CF₃, —CO₂H, —COCH₃, —CO₂CH₃, —CO₂C(CH₃)₃, —COCH(OH)CH₃, —CONH₂,—CONHCH₃, —CON(CH₃)₂, —C(CH₃)₂CONH₂, —NO₂, —NH₂, —NHCH₃, —N(CH₃)₂,—NHCOCH₃, —N(CH₃)COCH₃, —NHS(O)₂CH₃, —N(CH₃)C(CH₃)₂CONH₂,—N(CH₃)CH₂CH₂S(O)₂CH₃, ═O, —OH, —OCH₃, —S(O)₂N(CH₃)₂₅—SCH₃, —CH₂OCH₃,and —S(O)₂CH₃.
 6. The compound of claim 1 wherein R³ is C₆-C₂₀ aryl. 7.The compound of claim 6 wherein R³ is phenyl substituted with one ormore F.
 8. The compound of claim 1 having the structure of Formula Ia:


9. The compound of claim 1 having the structure of Formula Ib:


10. The compound of claim 1 having the structure of Formula Ic:


11. The compound of claim 1 having the structure of Formula Id:


12. The compound of claim 1 selected from:(S)-5-amino-N-(5-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(S)-5-amino-N-(5-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide;5-amino-N-(5-(4-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;3-amino-N-(5-(4-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-phenylpicolinamide;3-amino-N-(5-(4-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;(S)-3-amino-N-(5-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;(R)-3-amino-N-(5-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;3-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;(S)-3-amino-N-(5-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide;3-amino-N-(5-(4-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide;(R)-3-amino-N-(5-(3-aminopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;(S)-3-amino-N-(5-(3-aminopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;(R)-5-amino-N-(5-(3-aminopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(S)-5-amino-N-(5-(3-aminopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(S)-3-amino-N-(5-(3-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;(R)-3-amino-N-(5-(3-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;3-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;(S)-5-amino-N-(5-(3-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(3-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(S)-3-amino-N-(5-(3-(aminomethyl)pyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;(R)-5-amino-N-(5-(3-(aminomethyl)pyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(R)-3-amino-N-(5-(3-(aminomethyl)pyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;(S)-5-amino-N-(5-(3-(aminomethyl)pyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(S)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(R)-3-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide;(S)-3-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;(S)-3-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide;(R)-5-amino-N-(5-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(R)-3-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;(R)—N-(5-(3-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(R)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(S)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;and5-amino-N-(5-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;13. The compound of claim 1 selected from(S)-3-amino-N-(5-(3-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;(R)-5-amino-N-(5-(3-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(R)-3-amino-N-(5-(3-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;(S)-5-amino-N-(5-(3-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(piperazin-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;3-amino-6-(2-fluorophenyl)-N-(1-methyl-5-(piperazin-1-yl)-1H-pyrazol-4-yl)picolinamide;N-(5-(1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxamide;5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(1H-pyrrolo[3,4-c]pyridin-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;N-(3-(4-(aminomethyl)piperidin-1-yl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide;N-(5-(1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-3-amino-6-(2-fluorophenyl)picolinamide;N-(3-(4-aminopiperidin-1-yl)-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide;5-amino-2-(2,6-difluorophenyl)-N-(5-(4-hydroxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;(R)—N-(5-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide;(S)—N-(5-(3-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide;N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide;N-(5-(4-(2-aminoethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide;N-(5-(1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide;(R)—N-(5-(3-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide;(S)—N-(5-(3-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide;N-(5-(4-aminopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-5-(2-fluorophenyl)nicotinamide;5-amino-2-(2,6-difluorophenyl)-N-(5-(4-(dimethylamino)azepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,4-difluorophenyl)thiazole-4-carboxamide;5-amino-N-(5-(4-(2-aminoethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluoro-4-methoxyphenyl)thiazole-4-carboxamide;5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(4-(N-methylacetamido)azepan-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(4-(trifluoromethyl)phenyl)thiazole-4-carboxamide;(R)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(4-(N-methylacetamido)azepan-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-(trifluoromethyl)phenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-4-methylphenyl)thiazole-4-carboxamide;(R)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-5-fluoro-6-(2-fluorophenyl)picolinamide;(R)-5-amino-N-(5-(3-(2-aminoethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;5-amino-N-(5-(azepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(R)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide;(S)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(4-cyclopropyl)-2-fluorophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;(S)-5-amino-2-(2,6-difluorophenyl)-N-(5-(4-(dimethylamino)azepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;(R)-5-amino-2-(2,6-difluorophenyl)-N-(5-(4-(dimethylamino)azepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide;(R)—N-(5-(4-acetamidoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxamide;5-amino-N-(5-(3-(2-aminoethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(R)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-5-fluoro-6-phenylpicolinamide;(R)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-cyclopentyl-5-fluoropicolinamide;(R)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(5-(dimethylcarbamoyl)-2-fluorophenyl)-5-fluoropicolinamide;(R)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-cyclopentenyl-5-fluoropicolinamide;(R)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide;5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-morpholino-1H-pyrazol-4-yl)thiazole-4-carboxamide;(R)-5-amino-2-(2,6-difluorophenyl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;5-amino-N-(5-(4-aminoazepan-1-yl)-1-ethyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(S)-5-amino-2-(2,6-difluorophenyl)-N-(5-(3-hydroxypyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;5-amino-2-(2,6-difluorophenyl)-N-(5-(4-fluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;5-amino-2-(2,6-difluorophenyl)-N-(5-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;(S)-5-amino-2-(2,6-difluorophenyl)-N-(5-(3-fluoropyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;(R)-5-amino-2-(2,6-difluorophenyl)-N-(5-(3-fluoropyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(piperidin-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-cyanophenyl)thiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-fluorophenyl)thiazole-4-carboxamide;5-amino-N-(5-(3-(2-aminoethyl)pyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-5-(trifluoromethyl)phenyl)thiazole-4-carboxamide;N-(5-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-1-methyl-1H-pyrazol-4-yl)-5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cyclopentenylthiazole-4-carboxamide;5-amino-2-(2,6-difluorophenyl)-N-(5-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cyclohexenylthiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cycloheptenylthiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-ethylphenyl)thiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-methoxyphenyl)thiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-isopropylphenyl)thiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-isopropyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-carbamoylphenyl)thiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-(dimethylamino)phenyl)thiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,5-dichlorophenyl)thiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(4-hydroxy-2-(trifluoromethyl)phenyl)thiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-fluoro-2-(trifluoromethyl)phenyl)thiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(4-methoxy-2-(trifluoromethyl)phenyl)thiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cyclohexylthiazole-4-carboxamide;5-amino-N-(5-(4,4-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;5-amino-2-(2,6-difluorophenyl)-N-(5-(3,3-difluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(3-oxopiperazin-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cyclopentylthiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-cyclopropyl-2-fluoro-3-methylphenyl)thiazole-4-carboxamide;(R)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(3-oxo-1,4-diazepan-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;5-amino-2-(2,6-difluorophenyl)-N-(5-(3-fluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(4-methylpiperazin-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-fluoro-2-hydroxyphenyl)thiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-cyano-2-fluorophenyl)thiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cycloheptylthiazole-4-carboxamide;5-amino-N-(5-(4-cyanopiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-isopropylphenyl)thiazole-4-carboxamide;(R)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-5-fluoropicolinamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cyclopropylthiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cyclobutylthiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-bromo-2-fluorophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-isopropyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-cyclopropyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(S)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-ethyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-chloro-2-fluorophenyl)thiazole-4-carboxamide;5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(1,4-oxazepan-4-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(5-oxo-1,4-diazepan-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;5-amino-2-(2,6-difluorophenyl)-N-(5-(4-(2-hydroxyethyl)piperazin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(4-methoxy-2-(trifluoromethyl)phenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-fluorophenyl)thiazole-4-carboxamide;(R)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(4-(methylamino)azepan-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;(S)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(4-(methylamino)azepan-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)pyrimidine-4-carboxamide;5-amino-2-(2,6-difluorophenyl)-N-(5-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-ethyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cyclopentenylthiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cyclohexenylthiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-cycloheptenylthiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-methylthiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,5-dichlorophenyl)thiazole-4-carboxamide;5-amino-N-(5-(5-amino-4,4-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;5-amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluoro-3-methoxyphenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-cyanophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-fluoro-2-hydroxyphenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-cyano-2-fluorophenyl)thiazole-4-carboxamide;(S)—N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-5-fluoro-6-(2-fluorophenyl)picolinamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-ethyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-cyclopropyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide;(S)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)pyrimidine-4-carboxamide;5-amino-N-(5-(2-(aminomethyl)morpholino)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-chloro-2-fluorophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-bromo-2-fluorophenyl)thiazole-4-carboxamide;(S)-5-amino-2-(2,6-difluorophenyl)-N-(5-(4-hydroxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;(R)-5-amino-2-(2,6-difluorophenyl)-N-(5-(4-hydroxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;5-amino-N-(5-(4-hydroxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(pyridin-2-yl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,3-difluorophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(pyridin-2-yl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-3-methylphenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-cyclopropyl)-2-fluorophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-ethyl-2-fluorophenyl)thiazole-4-carboxamide;N-(5-(1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-3-amino-6-(2-fluorophenyl)picolinamide;3-amino-6-(2-fluorophenyl)-N-(1-methyl-5-(1H-pyrrolo[3,4-c]pyridin-2(3H,3aH,4H,5H,6H,7H,7aH)-yl)-1H-pyrazol-4-yl)picolinamide;5-Amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(4-cyanophenyl)thiazole-4-carboxamide;5-Amino-N-(5-(4-(aminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-fluoro-2-methoxyphenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-cyclopropyl-2-fluorophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-cyclopropyl-1H-pyrazol-4-yl)-2-cyclopentenylthiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-ethyl-1H-pyrazol-4-yl)-2-cyclopentenylthiazole-4-carboxamide;5-amino-N-(5-(4-amino-3-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-ethyl-2-fluorophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-cyclopropyl-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-ethyl-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;5-amino-N-(5-((4S,5S)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;5-amino-N-(5-((4S,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-3-isopropylphenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-cyclopropyl-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-ethyl-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-cyclopropyl-2-fluorophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(5-ethyl-2-fluorophenyl)thiazole-4-carboxamide;5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(5-(trifluoromethyl)-1,4-diazepan-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide;5-amino-N-(5-(6,6-difluoro-1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;5-amino-2-(2-fluorophenyl)-N-(5-(4-hydroxy-4-methylazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;N-(5-(1,4-diazepan-1-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxamide;5-amino-N-(5-(5-amino-4,4-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;5-amino-N-(5-(5-amino-4,4-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;N-(5-(1,4-diazepan-1-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-5-amino-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;N-(5-(1,4-diazepan-1-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-5-amino-2-(2,5-difluorophenyl)thiazole-4-carboxamide;5-amino-N-(5-(3-aminoazepan-1-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;and5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(6-methyl-1,4-diazepan-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide.14. A pharmaceutical composition comprised of a compound of claim 1 anda pharmaceutically acceptable carrier, glidant, diluent, or excipient.15. A process for making a pharmaceutical composition which comprisescombining a compound of claim 1 with a pharmaceutically acceptablecarrier, glidant, diluent, or excipient.
 16. A process for making acompound selected from Formula I:

and stereoisomers, geometric isomers, tautomers, or pharmaceuticallyacceptable salts thereof, wherein: R¹ is H, C₁-C₁₂ alkyl, C₂-C₁₂alkenyl, C₂-C₁₂ alkynyl, C₆-C₂₀ aryl, C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, or C₁-C₂₀ heteroaryl; R² is NR⁴R⁵, and R⁴ and R⁵ togetherform C₂-C₂₀ heterocyclyl or C₁-C₂₀ heteroaryl; X is:

where the wavy line indicates the site of attachment; R³ is C₆-C₂₀ aryl,—(C₆-C₂₀ arylene)-(C₂-C₂₀ heterocyclyl), —(C₆-C₂₀ arylene)-(C₁-C₁₂alkylene)-(C₂-C₂₀ heterocyclyl), C₃-C₁₂ carbocyclyl, C₂-C₂₀heterocyclyl, or C₁-C₂₀ heteroaryl; R⁶ is —NH₂; R⁷ is H, F, CH₂F, CHF₂,and CF₃; and where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl,heterocyclyl, aryl, and heteroaryl are optionally substituted with oneor more groups independently selected from F, Cl, Br, I, —CH₃, —CH₂CH₃,—CH(CH₃)₂, —CH₂CH(CH₃)₂, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CHCH₂NH₂,—CH₂CH(CH₃)NH₂, —CH₂OH, —CH₂CH₂OH, —C(CH₃)₂OH, —CH(OH)CH(CH₃)₂,—C(CH₃)₂CH₂OH, —CH₂CH₂SO₂CH₃, —CN, —CF₃, —CO₂H, —COCH₃, —CO₂CH₃,—CO₂C(CH₃)₃, —COCH(OH)CH₃, —CONH₂, —CONHCH₃, —CON(CH₃)₂, —C(CH₃)₂CONH₂,—NO₂, —NH₂, —NHCH₃, —N(CH₃)₂, —NHCOCH₃, —N(CH₃)COCH₃, —NHS(O)₂CH₃,—N(CH₃)C(CH₃)₂CONH₂, —N(CH₃)CH₂CH₂S(O)₂CH₃, ═O, —OH, —OCH₃,—S(O)₂N(CH₃)₂, —SCH₃, —CH₂OCH₃, —S(O)₂CH₃, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, azepanyl, oxetanyl,pyrrolidinyl, piperazinyl, piperidinyl, (piperidin-4-yl)ethyl), pyranyl,(piperidin-4-ylmethyl), morpholinomethyl, and morpholino; comprisingcoupling a 3,4-diaminopyrazole compound 14 and a 2-substituted,4-carboxy-5-aminothiazole compound 15 where R is Br or R³, to formintermediate 16:


17. The process of claim 16 wherein R is Br, comprising reactingintermediate 16 by a palladium-catalyzed Suzuki coupling reaction with aaryl, heterocyclyl or heteroaryl boronic acid or ester reagent to formintermediate 17:

and treatment of 17 with an acidic reagent to remove the Boc protectinggroup whereby the Formula I compound is formed.